National Institute For Health And Clinical Excellence Appraisal Committee Research Articles

The Clinical and Cost Effectiveness of Apremilast for Treating Active Psoriatic Arthritis: A Critique of the Evidence.

As part of the National Institute for Health and Clinical Excellence (NICE) single technology appraisal (STA) process, the manufacturer of apremilast was invited to submit evidence for its clinical and cost effectiveness for the treatment of active psoriatic arthritis (PsA) for whom disease-modifying anti-rheumatic drugs (DMARDs) have been inadequately effective, not tolerated or contraindicated. The Centre for Reviews and Dissemination and Centre for Health Economics at the University of York were commissioned to act as the independent Evidence Review Group (ERG). This paper provides a description of the ERG review of the company's submission, the ERG report and submission and summarises the NICE Appraisal Committee's subsequent guidance (December 2015). In the company's initial submission, the base-case analysis resulted in an incremental cost-effectiveness ratio (ICER) of £14,683 per quality-adjusted life-year (QALY) gained for the sequence including apremilast (positioned before tumour necrosis factor [TNF]-α inhibitors) versus a comparator sequence without apremilast. However, the ERG considered that the base-case sequence proposed by the company represented a limited set of potentially relevant treatment sequences and positions for apremilast. The company's base-case results were therefore not a sufficient basis to inform the most efficient use and position of apremilast. The exploratory ERG analyses indicated that apremilast is more effective (i.e. produces higher health gains) when positioned after TNF-α inhibitor therapies. Furthermore, assumptions made regarding a potential beneficial effect of apremilast on long-term Health Assessment Questionnaire (HAQ) progression, which cannot be substantiated, have a very significant impact on results. The NICE Appraisal Committee (AC), when taking into account their preferred assumptions for HAQ progression for patients on treatment with apremilast, placebo response and monitoring costs for apremilast, concluded that the addition of apremilast resulted in cost savings but also a QALY loss. These cost savings were not high enough to compensate for the clinical effectiveness that would be lost. The AC thus decided that apremilast alone or in combination with DMARD therapy is not recommended for treating adults with active PsA that has not responded to prior DMARD therapy, or where such therapy is not tolerated.

Dabigatran etexilato per la prevenzione del tromboembolismo venoso in pazienti sottoposti a sostituzione elettiva di anca o ginocchio

The National Institute for Health and Clinical Excellence (NICE) invited Boehringer Ingelheim GmbH, the manufacturer of dabigatran etexilate (DBG), to submit evidence on the clinical and cost effectiveness of this drug for the primary prevention of venous thromboembolism (VTE) in adult patients who have undergone total hip replacement (THR) or total knee replacement (TKR) surgery, as part of NICE’s single technology appraisal process. The comparators were enoxaparin and fondaparinux, as identified in the scope issued by NICE. The School of Health and Related Research at the University of Sheffield was commissioned to act as the Evidence Review Group (ERG). This article provides a description of the company submission, the ERG review and NICE’s subsequent decisions. Clinical-effectiveness evidence for DBG versus enoxaparin was derived from two randomized, double-blind, noninferiority trials, one for THR and the other for TKR. Clinical-effectiveness evidence for DBG versus fondaparinux was taken from a mixed treatment comparison (MTC) and from one study. The results presented show that DBG at the licensed dose of 220 mg and 150 mg once daily was noninferior to enoxaparin (40 mg once daily) in terms of the primary efficacy outcome of total VTE and all-cause mortality. In the MTC, fondaparinux was found to be more effective than DBG; the level of statistical significance was not reported. The manufacturer’s cost-effectiveness model estimated that at a dose of 220 mg once a day, DBG dominated enoxaparin in both THR and TKR. At a dose of 150 mg daily, DBG dominated enoxaparin in THR, while enoxaparin dominated DBG in TKR. At a dose of 220 mg daily, DBG was less cost effective than fondaparinux in THR. The cost per QALY gained for fondaparinux versus DBG was £11 111 (year 2008 values). At a dose of 150 mg daily, DBG was less cost effective than fondaparinux in THR. The cost per QALY gained for fondaparinux versus DBG was £6857 (year 2008 values). In TKR, both DBG doses were dominated by fondaparinux. There was some evidence that DBG was more cost effective than enoxaparin; however, these results were based on only one trial each in THR and TKR. Fondaparinux appeared to be more cost effective than DBG; however, this was based on indirect comparisons. NICE concluded that although there was uncertainty in the evidence base, DBG was very likely to be of equivalent clinical and cost effectiveness to enoxaparin or fondaparinux in the prevention of VTE. The NICE Appraisal Committee (AC) acknowledged that oral administration of DBG, without the need for monitoring, would reduce administration costs and that it may support adherence to treatment. Therefore, the AC concluded that DBG should be recommended as an option in the circumstances in which enoxaparin (or fondaparinux as an alternative) may be offered.

Cabazitaxel for the Second-Line Treatment of Metastatic Hormone-Refractory Prostate Cancer: A NICE Single Technology Appraisal

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of cabazitaxel (Jevtana®, sanofi-aventis, UK) to submit evidence of its clinical and cost effectiveness for the second-line treatment of metastatic hormone-refractory prostate cancer (mHRPC). The School of Health and Related Research Technology Appraisal Group (ScHARR-TAG) at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a critical review of the evidence for the clinical and cost effectiveness of the technology based upon the manufacturer's submission to NICE. Clinical evidence was derived from a multinational randomized open-label phase III trial of cabazitaxel plus prednisone or prednisolone in men with mHRPC that had progressed during or following treatment with docetaxel. The comparator was mitoxantrone plus prednisone or prednisolone. Use of cabazitaxel was associated with a statistically significant improvement in overall survival, median progression-free survival and time to tumour progression. However, it was also associated with an increased incidence of adverse events such as neutropenia. Utility data were based on interim results from the early access programme for cabazitaxel. Data were only available for a small number of patients with stable disease, resulting in great uncertainty as to the effect of cabazitaxel on quality of life. For their economic evaluation, the manufacturer estimated that the use of cabazitaxel was associated with an incremental cost of £74,908 per QALY gained. However, the ERG disagreed with the manufacturer over two key methodological points. The first concerned modelling and extrapolating survival; the second point was concerned with the choice of patient population. The ERG altered the manufacturer's evaluation to take into account these two points of disagreement. The resulting cost per QALY gained was £82,950. The NICE Appraisal Committee believed the analysis presented by the ERG to be more plausible, and likely to be an underestimate of the cost per QALY. They concluded that whilst the clinical effectiveness of cabazitaxel had been proven, it was not likely to represent a cost-effective use of NHS resources and so its use could not be recommended.

Trabectedin for the Treatment of Advanced Metastatic Soft Tissue Sarcoma: A NICE Single Technology Appraisal

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of trabectedin (PharmaMar) to submit evidence for the clinical and cost effectiveness of this drug for the treatment of advanced metastatic soft tissue sarcoma (aMSTS), as part of the Institute's single technology appraisal (STA) process. The School of Health and Related Research (ScHARR) was commissioned to act as the Evidence Review Group (ERG). This paper provides a description of the company submission, the ERG review and NICE's subsequent decisions. The ERG produced a review of the evidence for the clinical and cost effectiveness of the technology contained within the manufacturer's submission to NICE. The ERG also independently modified the manufacturer's decision analytic model to examine the impact of altering some of the key assumptions. The main evidence was derived from a single phase II randomized controlled trial (RCT) conducted in liposarcoma and leiomyosarcoma only, in which the licensed dose of trabectedin was compared with a different dose of trabectedin. Additional data were also presented from three uncontrolled phase II trials. Supplementary studies were used to represent best supportive care (BSC). The median overall survival (OS) was 13.9months for the licensed dose of trabectedin in the main randomized controlled trial (RCT) and ranged from 9.2months to 12.8months in the other studies included. Supplementary studies supplied by the manufacturer, and assumed to represent BSC, had median OS of 5.9-6.6months. The progression-free survival (PFS) rates at 6months for trabectedin were 35.5% in the main RCT and 24.4-29% in the other studies included. The PFS rates at 6months were 8-14% for BSC. In the manufacturer's original submission to NICE, the base-case incremental cost-effectiveness ratio (ICER) of trabectedin compared with BSC was approximately £44,000 per QALY gained. After amendment of errors identified by the ERG, the ICER reported by the manufacturer increased to approximately £61,000. The ERG concluded that, despite clarifications from the manufacturer and the revisions made to the model, there was still considerable uncertainty in the ICER. The NICE Appraisal Committee (AC) gave a negative initial recommendation, although indicated that trabectedin in aMSTS met the end-of-life criteria. Subsequently, the manufacturer submitted a patient access scheme (PAS) where any cycles beyond the fifth were provided at no cost by the manufacturer. This improved the ICER to approximately £34,000 per QALY gained. The AC gave a positive recommendation, subject to the implementation of the PAS.

Retigabine for the Adjunctive Treatment of Adults with Partial-Onset Seizures in Epilepsy with and without Secondary Generalization

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of retigabine (GlaxoSmithKline) to submit evidence for the clinical and cost effectiveness of this drug for the treatment of adults with partial-onset seizures in epilepsy, with and without secondary generalization, as part of the Institute's single technology appraisal (STA) process. The Centre for Reviews and Dissemination was commissioned to act as the Evidence Review Group (ERG). The ERG undertakes a critical review of the clinical and cost-effectiveness evidence of the technology based upon the manufacturer's submission to NICE. The ERG also independently searches for relevant evidence and evaluates modifications to the manufacturer's decision-analytic model. This paper provides a description of the company submission, the ERG review and NICE's subsequent decisions. The clinical effectiveness data were derived from three placebo-controlled randomized controlled trials (RCTs). A meta-analysis pooling across all doses of retigabine found beneficial effects of retigabine in terms of responder rate (odds ratio [OR] 2.79; 95% CI 2.08, 3.76) and rate of seizure freedom (OR 2.54; 95% CI 0.92, 6.98) [both double-blind phase analyses]. When compared in a network meta-analysis with the selected comparator antiepileptic drugs (AEDs) [eslicarbazepine acetate, lacosamide, pregabalin, tiagabine and zonisamide], retigabine offered broadly similar efficacy in terms of responder rate and freedom from seizure. The de novo decision-analytic model presented within the submission evaluated the cost effectiveness of retigabine compared with these AEDs and no treatment (i.e. maintenance therapy). After numerous additional analyses, the ERG considered the use of retigabine to be not cost effective for NICE at thresholds below £43,000 if no treatment was considered a relevant comparator. The NICE Appraisal Committee decided that an appropriate comparator was an active treatment. The Committee recommended that retigabine is offered as an option for the adjunctive treatment of partial-onset seizures with or without secondary generalization in adults aged 18years and older with epilepsy, only when previous treatment with carbamazepine, clobazam, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, sodium valproate and topiramate has not provided an adequate response, or has not been tolerated.

Pazopanib for the First-Line Treatment of Patients with Advanced and/or Metastatic Renal Cell Carcinoma

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of pazopanib hydrochloride (GlaxoSmithKline) to submit evidence of the clinical and cost effectiveness of the drug for the first-line treatment of advanced and/or metastatic renal cell carcinoma, as part of the Institute's single technology appraisal (STA) process. The Aberdeen Health Technology Assessment Group were commissioned to act as the Evidence Review Group (ERG). This article provides a description of the company submission, the ERG review and NICE's subsequent decisions. The objective of this paper is to summarize the independent review and critique of the evidence submitted for the consideration of the NICE Appraisal Committee and NICE's subsequently issued guidance. The ERG produced a critical review of the evidence for the clinical and cost effectiveness of the technology based upon the manufacturer's submission to NICE. The ERG also independently searched for relevant evidence and modified the manufacturer's decision analytic model to examine the impact of altering some of the key assumptions. For progression-free survival (PFS), there was a statistically significant longer survival for pazopanib compared with placebo (as assessed by the ERG, based upon the original manufacturer submission with a clinical cut-off date of 23 May 2008) [median 11.1 vs. 2.8months; hazard ratio (HR) 0.40; 95 % CI 0.27, 0.60]. Data from the indirect comparison suggested that pazopanib had a greater survival than interferon alpha (IFN-α) [HR 0.512; 95 % CI 0.326, 0.802] but provided no evidence of any difference compared with sunitinib (HR 0.949; 95 % CI 0.575, 1.568). With regard to overall survival, 64 % (n=99) of patients in the pazopanib arm and 63 % (n=49) of patients in the placebo arm had died and a total of 51 % (n=40) of placebo patients had crossed over to receive pazopanib. Although data were provided on an intention-to-treat basis, crossover between therapies made such data difficult to interpret. There was no evidence of any statistically significant difference between pazopanib and best supportive care (HR 0.501; 95 % CI 0.136, 2.348). In the indirect comparison, there were no statistically significant differences between pazopanib and IFN-α (HR 0.627; 95 % CI 0.173, 2.269) or between pazopanib and sunitinib (HR 0.969; 95 % CI 0.359, 2.608). Based upon the work presented including a 12.5 % discount for pazopanib, sunitinib was extendedly dominated by a combination of pazopanib and IFN-α. As a consequence, the incremental cost per QALY for pazopanib versus IFN-α was £38,925. The results were not greatly altered over the range of univariate deterministic sensitivity analyses conducted by the manufacturer but pair-wise probabilistic sensitivity analyses suggested that given a threshold value of £30,000, there is a 54 % probability that pazopanib was preferred to sunitinib, 40 % chance against IFN-α and 47 % chance against best supportive care. The Appraisal Committee concluded that pazopanib should be recommended as a first-line treatment option for people with advanced renal cell carcinoma who have not received prior cytokine therapy and have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and if the manufacturer provides pazopanib with a 12.5 % discount on the list price and provides a possible future rebate linked to the outcome of the head-to-head COMPARZ trial, as agreed under the terms of the patient access scheme and to be confirmed when the COMPARZ trial data are made available.

Bevacizumab for Metastatic Colorectal Cancer

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of bevacizumab (Roche Products) to submit evidence for the clinical and cost effectiveness of this drug for the treatment of patients with metastatic colorectal cancer (mCRC), as part of the Institute's Single Technology Appraisal (STA) process. The School of Health and Related Research (ScHARR) at the University of Sheffield was commissioned to act as the Evidence Review Group (ERG). This paper provides a description of the company submission, the ERG review and NICE's subsequent decisions. The ERG produced a critical review of the evidence for the clinical and cost effectiveness of the technology provided within the manufacturer's submission to NICE. The ERG also independently searched for relevant evidence and modified the manufacturer's decision analytic model to examine the impact of altering some of the key assumptions. The main clinical effectiveness data were derived from a phase III, multicentre, multinational, two-arm, randomized, open-label study with the primary objective of confirming the non-inferiority of oxaliplatin plus capecitabine (XELOX) compared with oxaliplatin plus 5-fluorouracil and folinic acid (FOLFOX-4) in adult patients with histologically confirmed mCRC who had not previously been treated. The ERG considered that the NO16966 trial was of reasonable methodological quality and demonstrated a significant improvement in both progression-free and overall survival when bevacizumab is added to either XELOX or FOLFOX-4. The ERG considered that the size of the actual treatment effect of bevacizumab was uncertain due to trial design limitations, imbalance of a known prognostic factor, relatively short treatment duration compared with that allowed within the trial protocol, and interpretation of the statistical analyses. The manufacturer's submission included a de novo economic evaluation using a cost-effectiveness model built in Microsoft® Excel. The ERG believed that the modelling structure employed was appropriate but highlighted several areas of uncertainty that had the potential to have a significant impact on the resulting incremental cost-effectiveness ratios (ICERs). The areas of uncertainty identified by the ERG included whether chemotherapy would be administered continuously or intermittently, patient access scheme (PAS) costs and uptake, survival that was dependent on the statistical analyses used, and the likely duration of continued treatment with bevacizumab after cessation of oxaliplatin and the efficacy associated with continuation. The STA described here highlighted the challenges in appraising interventions with a complex PAS. Based on the analyses that include a discount to the list price of oxaliplatin, the ERG concluded that the ICERs for the addition of bevacizumab to XELOX or FOLFOX were both over £50 000. The NICE Appraisal Committee concluded that bevacizumab in combination with oxaliplatin and either 5-fluorouracil plus folinic acid or capecitabine (i.e. FOLFOX or XELOX) was not recommended for the treatment of mCRC.

Omalizumab for the Treatment of Severe Persistent Allergic Asthma in Children Aged 6–11 Years

Following a licence extension to include those aged 6-11 years, the National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of omalizumab (Novartis Pharmaceuticals UK) to submit evidence for the clinical and cost effectiveness of this drug for patients with severe persistent allergic asthma in this age bracket. NICE had previously considered the use of omalizumab in patients aged 12 years and over. The Centre for Reviews and Dissemination (CRD) and the Centre for Health Economics (CHE) at the University of York were commissioned as the Evidence Review Group (ERG) to critically appraise the evidence presented by the manufacturer. This article summarizes that review of the evidence, the deliberations of the NICE Appraisal Committee and the resulting NICE guidance. The ERG critically reviewed the evidence presented in the manufacturer's submission and identified areas requiring clarification, for which the manufacturer provided additional evidence. The relevant patient population was patients aged 6-11 years of age with severe persistent allergic immunoglobulin E-mediated asthma whose condition remained uncontrolled despite best standard care with high-dose inhaled corticosteroids and a long-acting inhaled β₂-agonist. The main clinical effectiveness data were derived from a pre-planned subgroup analysis of a single randomized controlled trial comparing omalizumab plus standard therapy against standard therapy alone. At a 52-week follow-up, the only outcome to show a statistically significant benefit of omalizumab compared with placebo was the number of exacerbations defined as 'clinically significant' [CS] (relative risk [RR] 0.504; 95% CI 0.350, 0.725; p < 0.001). At the ERG's request, the manufacturer provided analyses stratified by baseline exacerbation rate, which indicated the effect of omalizumab on CS exacerbations was statistically significant only for those children with ≥3 exacerbations as baseline. The ERG identified a number of issues relating to the clinical effectiveness results: it was unclear whether the pre-planned subgroup analysis had sufficient power; the definition of CS exacerbation was less severe than that used in UK clinical practice; and the method for imputing exacerbations for those who withdrew from treatment may have underestimated the exacerbation rate. The incremental cost-effectiveness ratio based on the manufacturer's results was considerably above the threshold range stated in the NICE Guide to the Methods of Technology Appraisal. The ERG identified numerous issues relating to the cost-effectiveness results, which included the following: the 10-year time horizon for treatment may exceed that in clinical practice; the assumption of constant exacerbation rates over a lifetime given that adolescence is expected to impact on the severity of asthma; and whether it is appropriate to use health-related quality-of-life data collected in adults for children. The ERG concluded that omalizumab appears to reduce CS exacerbations but there was no evidence of improvement in daily symptoms, CS severe (CSS) exacerbations or hospitalization rates. The main driver of cost effectiveness was the reduction in asthma-related mortality associated with a reduction in CSS exacerbations. As the number of CSS exacerbations avoided was low, as is asthma-related mortality in children, the potential small gain in QALYs associated with omalizumab was not sufficient to compensate for the high treatment cost even under the most favourable scenario analyses. The Appraisal Committee recommended that omalizumab should not be routinely provided for the treatment of severe persistent allergic asthma in children aged 6-11 years.

Dabigatran Etexilate for the Prevention of Venous Thromboembolism in Patients Undergoing Elective Hip or Knee Surgery

The National Institute for Health and Clinical Excellence (NICE) invited Boehringer Ingelheim GmbH, the manufacturer of dabigatran etexilate (DBG), to submit evidence on the clinical and cost effectiveness of this drug for the primary prevention of venous thromboembolism (VTE) in adult patients who have undergone total hip replacement (THR) or total knee replacement (TKR) surgery, as part of NICE's single technology appraisal process. The comparators were enoxaparin and fondaparinux, as identified in the scope issued by NICE. The School of Health and Related Research at the University of Sheffield was commissioned to act as the Evidence Review Group (ERG). This article provides a description of the company submission, the ERG review and NICE's subsequent decisions. Clinical-effectiveness evidence for DBG versus enoxaparin was derived from two randomized, double-blind, noninferiority trials, one for THR and the other for TKR. Clinical-effectiveness evidence for DBG versus fondaparinux was taken from a mixed treatment comparison (MTC) and from one study. The results presented show that DBG at the licensed dose of 220 mg and 150 mg once daily was noninferior to enoxaparin (40 mg once daily) in terms of the primary efficacy outcome of total VTE and all-cause mortality. In the MTC, fondaparinux was found to be more effective than DBG; the level of statistical significance was not reported. The manufacturer's cost-effectiveness model estimated that at a dose of 220 mg once a day, DBG dominated enoxaparin in both THR and TKR. At a dose of 150 mg daily, DBG dominated enoxaparin in THR, while enoxaparin dominated DBG in TKR. At a dose of 220 mg daily, DBG was less cost effective than fondaparinux in THR. The cost per QALY gained for fondaparinux versus DBG was £11,111 (year 2008 values). At a dose of 150 mg daily, DBG was less cost effective than fondaparinux in THR. The cost per QALY gained for fondaparinux versus DBG was £6857 (year 2008 values). In TKR, both DBG doses were dominated by fondaparinux. There was some evidence that DBG was more cost effective than enoxaparin; however, these results were based on only one trial each in THR and TKR. Fondaparinux appeared to be more cost effective than DBG; however, this was based on indirect comparisons. NICE concluded that although there was uncertainty in the evidence base, DBG was very likely to be of equivalent clinical and cost effectiveness to enoxaparin or fondaparinux in the prevention of VTE. The NICE Appraisal Committee (AC) acknowledged that oral administration of DBG, without the need for monitoring, would reduce administration costs and that it may support adherence to treatment. Therefore, the AC concluded that DBG should be recommended as an option in the circumstances in which enoxaparin (or fondaparinux as an alternative) may be offered.

Dronedarone for the Treatment of Atrial Fibrillation

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of dronedarone (Multaq®, Sanofi-Aventis Limited, UK) to submit evidence on the clinical and cost effectiveness of the anti-arrhythmic drug (AAD) for the treatment of atrial fibrillation (AF) and atrial flutter, as part of the Institute's single technology appraisal (STA) process. The Centre for Reviews and Dissemination and the Centre for Health Economics, both at the University of York, were commissioned to act as the independent Evidence Review Group (ERG). This article provides a description of the company submission, the ERG review and NICE's subsequent decisions regarding the use of dronedarone within the UK NHS. The ERG review comprised a critique of the submitted evidence on the clinical effectiveness and cost effectiveness of dronedarone. The ERG examined the search strategy used to obtain relevant evidence, the selection of studies included in the assessment, outcome measures chosen and statistical methods employed. The ERG also validated the manufacturer's decision analytic model and used it to explore the robustness of the cost-effectiveness results to key assumptions. The main clinical effectiveness evidence supporting the use of dronedarone as a treatment for AF came from four randomized controlled trials. These trials were compared with a broader set of trials examining the effectiveness of other AADs for AF: amiodarone, sotalol and class 1c agents (flecainide and propafenone). The evidence suggested that all AADs decreased the recurrence of AF but dronedarone had the smallest effect. A mixed treatment comparison analysis of the trials showed that dronedarone was associated with a lower risk of all-cause mortality than other AADs, but this was highly uncertain. There was limited evidence to assess the effect of dronedarone on stroke, and no statistically significant differences between dronedarone and other AADs were found for treatment discontinuation. From the evidence presented by the manufacturer, dronedarone appeared highly cost effective in each of the population groups examined compared with using standard baseline therapy alone as first-line treatment, or compared with sotalol or amiodarone as first-line AAD, with incremental cost-effectiveness ratios (ICERs) well below £20,000 per QALY gained. The ICER for dronedarone relative to class 1c agents was around £19,000 per QALY. Although the evidence presented by the manufacturer indicated that dronedarone was cost effective, the estimates of treatment effect relative to other AADs and safety in the longer term were highly uncertain. The NICE Appraisal Committee in its preliminary guidance did not recommend the use of dronedarone for AF. However, following the response from a large number of consultees and commentators, NICE revised its preliminary guidance to allow the use of the drug in a specific subgroup of AF patients with additional cardiovascular risk factors.

Denosumab for the Prevention of Osteoporotic Fractures in Post-Menopausal Women

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of denosumab (Amgen Inc., UK) to submit evidence for the clinical and cost effectiveness of denosumab for the prevention of fragility fractures in post-menopausal women, as part of the Institute's single technology appraisal (STA) process. The University of Aberdeen Health Technology Assessment Group were commissioned to act as the Evidence Review Group (ERG); the role of the ERG being to appraise the manufacturer's submission and to produce an independent report. This article provides a description of the company submission, the ERG review and NICE's subsequent decisions. The manufacturer considered that denosumab would be appropriate for patients unable to take, comply with or tolerate oral bisphosphonates. Comparator treatments selected for the submission were, therefore, 'no treatment', raloxifene, strontium ranelate, intravenous zoledronic acid, intravenous ibandronate and teriparatide. The main effectiveness evidence for denosumab was derived from a large randomized controlled trial comparing denosumab with placebo. Given by subcutaneous injection at 6-monthly intervals for 3 years, denosumab reduced the incidence of hip fracture by 40%, and reduced the incidence of clinical vertebral fracture by 69%. An indirect treatment comparison was used to derive adjusted relative risk (RR) estimates for different types of fracture for each comparator versus placebo. The RRs (95% CI) applied for denosumab were 0.316 (0.208, 0.478) for clinical vertebral fracture, 0.605 (0.373, 0.983) for hip fracture and 0.842 (0.638, 1.110) for wrist fracture. Despite a number of concerns surrounding the methodology of the indirect comparison, the ERG was satisfied with the robustness of the effect estimates. The RR estimates were applied in a good-quality Markov model that took account of drug costs, administration and monitoring costs, costs associated with fractures, and long-term nursing home costs. Utility weights were used to adjust time spent in fracture states, allowing QALYs to be estimated. The base-case analysis was conducted for women aged 70 years with a T-score of -2.5 or less and no prior fracture, and women aged 70 years with a T-score of -2.5 or less with a prior fragility fracture. Subgroup analyses based on T-score and independent clinical risk factors were also undertaken. Applying a willingness-to-pay (WTP) threshold of £30 000 per QALY, the manufacturer's results suggested that denosumab would offer a cost-effective alternative to all treatment comparators for the primary and secondary prevention of fractures. The ERG was concerned about an assumption that denosumab would be administered in general practice at the average cost of two standard GP visits a year. As a result, the ERG requested some further sensitivity analysis and undertook some further modelling, applying an assumption that denosumab would be provided primarily in secondary care. This modification altered the cost effectiveness of denosumab versus 'no treatment' (in women with no prior fragility fracture) and zoledronic acid. The NICE Appraisal Committee concluded that, as a treatment option for the prevention of osteoporotic fractures, denosumab should be recommended only in post-menopausal women at increased risk of fracture who cannot comply with the special instructions for administering oral bisphosphonates, or have an intolerance of, or contraindication to, those treatments. For primary prevention, the Appraisal Committee also stipulated specific levels of fracture risk at which denosumab is recommended.

Febuxostat for the Management of Hyperuricaemia in Patients with Gout

As part of the National Institute for Health and Clinical Excellence (NICE) single technology appraisal (STA) process, the manufacturer of febuxostat (Adenuric®; Ipsen, UK) was invited to submit evidence for the clinical and cost effectiveness of febuxostat for the management of hyperuricaemia in patients with gout. The School of Health and Related Research Technology Appraisal Group (ScHARR-TAG) at the University of Sheffield were commissioned to act as the independent Evidence Review Group (ERG). This article provides details of the company's initial submission, the ERG's clarification questions and the ERG report submitted to NICE. The decision made by NICE is provided alongside a brief comment on additional results produced by a substantially different model, which were presented by the manufacturer after the production of the appraisal consultation document. The ERG produced a critical review of the evidence for the clinical evidence and cost effectiveness of the technology based upon the manufacturer's submission to NICE. The clinical evidence was derived from two head-to-head, phase III, multi-arm, randomized, double blind, controlled trials comparing the efficacy and safety of febuxostat with fixed-dose allopurinol (300/100 mg/day) in patients with hyperuricaemia and gout. The ERG considered that the trials were of reasonable methodological quality and measured a clinically relevant range of outcomes. Although a simple pooled analysis of the individual patient-level data from the two trials was undertaken, the statistical approach for combining the data was considered inappropriate by the ERG as it failed to preserve randomization and introduced bias and confounding. There was substantial uncertainty in the relationships reported by the manufacturer regarding serum uric acid levels and the incidence of gout flares and underlying patient utility. The mathematical model developed was flawed and was not corrected despite ERG comments. It focused only on patients receiving febuxostat (80 mg/day titrated to 120 mg/day if necessary) with fixed-dose allopurinol (300/100 mg/day). Sequential treatment was not modeled, nor was titrating allopurinol to 900 mg/day, which is regarded as best practice. Numerous other errors were identified, which included the uncertain price of febuxostat being sampled within the probabilistic sensitivity analyses. Supplementary exploratory modelling addressing the position of febuxostat where patients were intolerant or contraindicated to allopurinol was provided to the NICE Appraisal Committee following the release of the appraisal consultation document. The NICE Appraisal Committee concluded that febuxostat be recommended as an option for the management of chronic hyperuricaemia in gout only for people who are intolerant to allopurinol or for whom allopurinol is contraindicated.

Pharmacoeconomics: NICE's approach to decision‐making

The National Institute for Health and Clinical Excellence (NICE) is a decision-maker. Where NICE reaches a positive conclusion about the use of a particular health technology (such as a pharmaceutical product) in the National Health Service (NHS), there is a legal requirement for the service to make it available if a patient's physician considers it clinically appropriate [1]. Although this legal obligation does not apply to technologies recommended in NICE's clinical guidelines, there is still a reasonable expectation by the Care Quality Commission for NHS healthcare professionals to use NICE's clinical guidelines as the basis, where appropriate, for their clinical practice. NICE's independent advisory bodies (the Appraisal Committees, the Public Health Advisory Committee and Guideline Development Groups) are required to take account of both clinical and cost-effectiveness in reaching their conclusions about the use of health technologies generally and of pharmaceuticals in particular [2–4]. These advisory bodies must fully assess the available evidence on benefits and costs in order to come to a decision as to whether the use of a technology is considered a cost-effective use of resources. However, the scientific evidence underpinning any decision about the use of a particular health technology is never perfect. Nor is it all-embracing. Advisory bodies therefore need to use their experience to make judgements beyond the existing evidence. These judgements are of two types [5]: Scientific value judgements are ones about what can be inferred from the available evidence base; and the extent to which imperfections in the evidence base should influence decisions. Social value judgements are concerned with what is appropriate and acceptable for society in delivering healthcare across the NHS.

The NICE ADHD health technology assessment: A review and critique

BackgroundHealth technology assessments (HTAs) by the National Institute for Health and Clinical Excellence (NICE) enjoy high levels of international attention. The present analysis addresses NICE's appraisal of methylphenidate, atomoxetine and dexamphetamine for attention-deficit/hyperactivity disorder (ADHD) in children and adolescents, published in March 2006.MethodsA qualitative study of NICE Technology Appraisal No. 98 was done focusing on the >600-page technology assessment report, which aimed at evaluating ADHD treatment strategies by a clinical effectiveness review and an economic analysis using meta-analytical techniques and a cost-effectiveness model.ResultsThe technology assessment was unable to differentiate between the various drugs in terms of efficacy, and its economic model was ultimately driven by cost differences. While the assessment concluded that the economic model "clearly identified an optimal treatment strategy" with first-line dexamphetamine, the NICE appraisal committee subsequently found it impossible to distinguish between the different strategies on grounds of cost-effectiveness. Analyzing the assessment reveals gaps and inconsistencies concerning data selection (ultimately relying on a small number of short-term studies only), data synthesis (pooling of heterogeneous study designs and clinical endpoints), and economic model structure (identifying double-counting of nonresponders as a likely source of bias, alongside further methodological anomalies).ConclusionMany conclusions of the NICE technology assessment rest on shaky grounds. There remains a need for a new, state-of-the-art systematic review of ADHD treatment strategies including economic evaluation, which ideally should address outcomes beyond children's health-related quality of life, such as long-term sequelae of the disorder and caregiver burden.