Olaparib for Maintenance Treatment of BRCA 1 or 2 Mutated, Relapsed, Platinum-Sensitive Ovarian, Fallopian Tube and Peritoneal Cancer in People Whose Relapsed Disease has Responded to Platinum-Based Chemotherapy: An Evidence Review Group Perspective of a NICE Single Technology Appraisal

As part of its Single Technology Appraisal process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer of olaparib (AstraZeneca) to submit evidence on the clinical and cost effectiveness of olaparib for the maintenance treatment of BRCA1/2 mutated (BRCAm), platinum-sensitive relapsed (PSR) ovarian, fallopian tube and peritoneal cancer in people whose relapsed disease has responded to platinum-based chemotherapy. The Evidence Review Group (ERG) produced a critical review of the evidence contained within the company’s submission (CS) to NICE. The clinical evidence related to one phase II, double-blind randomised controlled trial that recruited 265 patients with PSR serous ovarian cancer (OC) regardless of BRCAm status. Patients received olaparib 400 mg twice daily (b.i.d.) or matched placebo. In the whole population, the primary endpoint of progression-free survival (PFS) was met (hazard ratio [HR] 0.35; 95 % confidence interval [CI] 0.25–0.49, p < 0.01) for olaparib versus placebo. The BRCAm subgroup analysis (added after the study commenced but 1 month before the primary analysis was undertaken) reported an HR for PFS of 0.18 (95 % CI 0.10–0.31, p < 0.0001) for olaparib versus placebo, though interaction tests appeared inconclusive. Overall survival was not statistically significant in the whole group (HR 0.88; 95 % CI 0.64–1.21; p = 0.44) or the BRCAm subgroup (0.73; 95 % CI 0.45–1.17; p = 0.19), though treatment switching may have confounded results. The exclusion of data from sites allowing crossover resulted in an HR for overall survival (OS) of 0.52 (95 % CI 0.28–0.97, p = 0.039) in the BRCAm group. Health-related quality-of-life measures were not significantly different between groups. All post hoc exploratory outcomes (time to treatment discontinuation/death, time to first subsequent therapy/death, and time to second subsequent therapy/death) were statistically significantly better in the olaparib arm in the whole population and the BRCAm subgroup analyses. Adverse events were more frequent for olaparib but were largely minor or manageable. The company’s semi-Markov model assessed the cost effectiveness of olaparib versus routine surveillance in patients with BRCAm PSR OC from a National Health Service (NHS) and Personal Social Services (PSS) perspective over a lifetime horizon. The model suggests that the incremental cost-effectiveness ratio (ICER) for olaparib versus routine surveillance is expected to be approximately £49,146 per quality-adjusted life-year (QALY) gained. The ERG did not consider the company’s cost-effectiveness estimates to be credible. Additional ERG analyses suggested that the ICER is likely to be more than £92,214 per QALY gained. Additional analyses provided by the company in patients who received three or more lines of chemotherapy suggested a more favourable cost-effectiveness profile for olaparib. The NICE Appraisal Committee recommended olaparib for this subgroup provided the cost of olaparib for people who continue to receive treatment after 15 months will be met by the company

Corrigendum: A systematic review and economic evaluation of bisphosphonates for the prevention of fragility fractures

Abstract Background Fragility fractures are fractures that result from mechanical forces that would not ordinarily result in fracture. Objectives To evaluate the clinical effectiveness and safety of bisphosphonates [alendronic acid (Fosamax® and Fosamax® Once Weekly, Merck Sharp & Dohme Ltd), risedronic acid (Actonel® and Actonel Once a Week®, Warner Chilcott UK Ltd), ibandronic acid (Bonviva®, Roche Products Ltd) and zoledronic acid (Aclasta®, Novartis Pharmaceuticals UK Ltd)] for the prevention of fragility fracture and to assess their cost-effectiveness at varying levels of fracture risk. Data sources For the clinical effectiveness review, six electronic databases and two trial registries were searched: MEDLINE, EMBASE, The Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, Web of Science and BIOSIS Previews, Clinicaltrials.gov and World Health Organization International Clinical Trials Registry Platform. Searches were limited by date from 2008 until September 2014. Review methods A systematic review and network meta-analysis (NMA) of effectiveness studies were conducted. A review of published economic analyses was undertaken and a de novo health economic model was constructed. Discrete event simulation was used to estimate lifetime costs and quality-adjusted life-years (QALYs) for each bisphosphonate treatment strategy and a strategy of no treatment for a simulated cohort of patients with heterogeneous characteristics. The model was populated with effectiveness evidence from the systematic review and NMA. All other parameters were estimated from published sources. A NHS and Personal Social Services perspective was taken, and costs and benefits were discounted at 3.5% per annum. Fracture risk was estimated from patient characteristics using the QFracture® (QFracture-2012 open source revision 38, Clinrisk Ltd, Leeds, UK) and FRAX® (web version 3.9, University of Sheffield, Sheffield, UK) tools. The relationship between fracture risk and incremental net benefit (INB) was estimated using non-parametric regression. Probabilistic sensitivity analysis (PSA) and scenario analyses were used to assess uncertainty. Results Forty-six randomised controlled trials (RCTs) were included in the clinical effectiveness systematic review, with 27 RCTs providing data for the fracture NMA and 35 RCTs providing data for the femoral neck bone mineral density (BMD) NMA. All treatments had beneficial effects on fractures versus placebo, with hazard ratios varying from 0.41 to 0.92 depending on treatment and fracture type. The effects on vertebral fractures and percentage change in BMD were statistically significant for all treatments. There was no evidence of a difference in effect on fractures between bisphosphonates. A statistically significant difference in the incidence of influenza-like symptoms was identified from the RCTs for zoledronic acid compared with placebo. Reviews of observational studies suggest that upper gastrointestinal symptoms are frequently reported in the first month of oral bisphosphonate treatment, but pooled analyses of placebo-controlled trials found no statistically significant difference. A strategy of no treatment was estimated to have the maximum INB for patients with a 10-year QFracture risk under 1.5%, whereas oral bisphosphonates provided maximum INB at higher levels of risk. However, the PSA suggested that there is considerable uncertainty regarding whether or not no treatment is the optimal strategy until the QFracture score is around 5.5%. In the model using FRAX, the mean INBs were positive for all oral bisphosphonate treatments across all risk categories. Intravenous bisphosphonates were estimated to have lower INBs than oral bisphosphonates across all levels of fracture risk when estimated using either QFracture or FRAX. Limitations We assumed that all treatment strategies are viable alternatives across the whole population. Conclusions Bisphosphonates are effective in preventing fragility fractures. However, the benefit-to-risk ratio in the lowest-risk patients may be debatable given the low absolute QALY gains and the potential for adverse events. We plan to extend the analysis to include non-bisphosphonate therapies. Study registration This study is registered as PROSPERO CRD42013006883. Funding The National Institute for Health Research Health Technology Assessment programme

Molecular testing for Lynch syndrome in people with colorectal cancer: systematic reviews and economic evaluation

This is the final version of the article. Available from the publisher via the DOI in this record.BACKGROUND: Inherited mutations in deoxyribonucleic acid (DNA) mismatch repair (MMR) genes lead to an increased risk of colorectal cancer (CRC), gynaecological cancers and other cancers, known as Lynch syndrome (LS). Risk-reducing interventions can be offered to individuals with known LS-causing mutations. The mutations can be identified by comprehensive testing of the MMR genes, but this would be prohibitively expensive in the general population. Tumour-based tests - microsatellite instability (MSI) and MMR immunohistochemistry (IHC) - are used in CRC patients to identify individuals at high risk of LS for genetic testing. MLH1 (MutL homologue 1) promoter methylation and BRAF V600E testing can be conducted on tumour material to rule out certain sporadic cancers. OBJECTIVES: To investigate whether testing for LS in CRC patients using MSI or IHC (with or without MLH1 promoter methylation testing and BRAF V600E testing) is clinically effective (in terms of identifying Lynch syndrome and improving outcomes for patients) and represents a cost-effective use of NHS resources. REVIEW METHODS: Systematic reviews were conducted of the published literature on diagnostic test accuracy studies of MSI and/or IHC testing for LS, end-to-end studies of screening for LS in CRC patients and economic evaluations of screening for LS in CRC patients. A model-based economic evaluation was conducted to extrapolate long-term outcomes from the results of the diagnostic test accuracy review. The model was extended from a model previously developed by the authors. RESULTS: Ten studies were identified that evaluated the diagnostic test accuracy of MSI and/or IHC testing for identifying LS in CRC patients. For MSI testing, sensitivity ranged from 66.7% to 100.0% and specificity ranged from 61.1% to 92.5%. For IHC, sensitivity ranged from 80.8% to 100.0% and specificity ranged from 80.5% to 91.9%. When tumours showing low levels of MSI were treated as a positive result, the sensitivity of MSI testing increased but specificity fell. No end-to-end studies of screening for LS in CRC patients were identified. Nine economic evaluations of screening for LS in CRC were identified. None of the included studies fully matched the decision problem and hence a new economic evaluation was required. The base-case results in the economic evaluation suggest that screening for LS in CRC patients using IHC, BRAF V600E and MLH1 promoter methylation testing would be cost-effective at a threshold of £20,000 per quality-adjusted life-year (QALY). The incremental cost-effectiveness ratio for this strategy was £11,008 per QALY compared with no screening. Screening without tumour tests is not predicted to be cost-effective. LIMITATIONS: Most of the diagnostic test accuracy studies identified were rated as having a risk of bias or were conducted in unrepresentative samples. There was no direct evidence that screening improves long-term outcomes. No probabilistic sensitivity analysis was conducted. CONCLUSIONS: Systematic review evidence suggests that MSI- and IHC-based testing can be used to identify LS in CRC patients, although there was heterogeneity in the methods used in the studies identified and the results of the studies. There was no high-quality empirical evidence that screening improves long-term outcomes and so an evidence linkage approach using modelling was necessary. Key determinants of whether or not screening is cost-effective are the accuracy of tumour-based tests, CRC risk without surveillance, the number of relatives identified for cascade testing, colonoscopic surveillance effectiveness and the acceptance of genetic testing. Future work should investigate screening for more causes of hereditary CRC and screening for LS in endometrial cancer patients. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016033879. FUNDING: The National Institute for Health Research Health Technology Assessment programme.Funding for this study was provided by the Health Technology Assessment programme of the National Institute for Health Researc

The Protease Inhibitor Monotherapy Versus Ongoing Triple Therapy (PIVOT) trial : a randomised controlled trial of a protease inhibitor monotherapy strategy for long-term management of human immunodeficiency virus infection

Background Standard-of-care antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection uses a combination of drugs, until now considered essential to minimise treatment failure and development of drug resistance. Protease inhibitors (PIs) are potent with a high genetic barrier to resistance and have the potential for use as monotherapy after viral load (VL) suppression achieved on combination therapy. However, longer-term resistance and toxicity risks are uncertain. Objective To compare the effectiveness, toxicity profile and cost-effectiveness of PI monotherapy with those of standard-of-care triple therapy in a pragmatic long-term clinical trial. Design Open-label, parallel-group, randomised controlled trial. Setting Forty-three HIV clinical centres in the UK NHS. Participants HIV-positive adults taking standard combination ART with a suppressed VL for ≥ 6 months. Interventions Patients were randomised to maintain ongoing triple therapy (OT) or switch to a strategy of physician-selected ritonavir-boosted PI monotherapy (PI-mono), with prompt return to combination therapy in the event of VL rebound. Main outcome measures The primary outcome was reduction of future drug options, defined as new intermediate-/high-level resistance to one or more drugs to which the patient’s virus was considered to be sensitive at trial entry (non-inferiority comparison, 10% margin). Secondary outcomes included confirmed virological rebound, serious drug- or disease-related complications, total grade 3 or 4 adverse events (AEs), neurocognitive function change, cluster of differentiation 4 (CD4) cell count change, change in health-related quality of life, cardiovascular risk change, health-care costs and health economic analysis. Results In total, 587 participants were randomised (77% male, 68% white) to OT (n = 291) or PI-mono (n = 296) and followed for a median of 44 months, of whom 2.7% withdrew/were lost to follow-up. One or more episodes of confirmed VL rebound were observed in eight patients (Kaplan–Meier estimate 3.2%) in the OT group and 95 patients (35.0%) in the PI-mono group [absolute risk difference 31.8%, 95% confidence interval (CI) 24.6% to 39.0%; p < 0.001]. PI-mono patients who changed to ART after VL rebound all resuppressed (median 3.5 weeks). The proportions with loss of a future drug option at 3 years were 0.7% in the OT group and 2.1% in the PI-mono group (difference 1.4%, (95% CI –0.4% to 3.4%); non-inferiority demonstrated). There were no significant differences in serious disease complications between groups or in the frequency of grade 3 or 4 clinical AEs (16.8% OT group vs. 22% PI-mono group; absolute risk difference 5.1%, 95% CI –1.3% to 11.5%; p = 0.12). Overall, the PI-mono strategy was shown to be cost-effective compared with OT under most scenarios explored. PI-mono was cost saving because of the large savings in ART drug costs while being no less effective in terms of quality-adjusted life-years in the within-trial analysis and only marginally less effective when extrapolated to lifetime outcomes. Conclusions PI monotherapy, with prompt reintroduction of combination therapy for VL rebound, was non-inferior to combination therapy in preserving future treatment options and is an acceptable and cost-effective alternative for long-term management of HIV infection. Trial registration Current Controlled Trials ISRCTN04857074. Funding This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 21. See the NIHR Journals Library website for further project information

Cost Effectiveness of Protease Inhibitor Monotherapy Versus Standard Triple Therapy in the Long-Term Management of HIV Patients : Analysis Using Evidence from the PIVOT Trial

Background Protease inhibitor (PI) monotherapy can maintain virological suppression in the majority of patients once it has been established on triple therapy and may also have the potential for substantial cost savings arising from the use of fewer drugs. However, the cost effectiveness of PI monotherapy has yet to be demonstrated. Objectives In this study we examine the cost effectiveness of PI monotherapy with prompt return to combination therapy in the event of viral load rebound compared with ongoing triple therapy (OT) in patients with suppressed viral load on combination antiretroviral therapy (ART) in the UK. Methods The analysis used data from the PIVOT trial in which HIV-positive adults with suppressed viral load for ≥24 weeks on combination ART were randomised to maintain OT or to a strategy of PI monotherapy with prompt return to combination therapy if viral load rebounded. A cost-effectiveness analysis including long-term modelling was conducted. Main outcomes included UK National Health Service (NHS) costs and quality-adjusted life-years (QALYs) with comparative results presented as incremental cost-effectiveness ratios. Results PI monotherapy was cost saving as a result of large savings in ART drug costs while being no less effective in terms of QALYs in the within-trial analysis and marginally less effective with lifetime modelling. In the base-case analysis over 3 years, the incremental total cost per patient was −£6424.11 (95 % confidence interval −7418.84 to −5429.38) and incremental QALYs were 0.0051 (95 % CI −0.0479 to 0.0582), resulting in PI monotherapy ‘dominating’ OT. Multiple scenario analyses found that PI monotherapy was cost saving with no marked differences in QALYs. Modelling of lifetime costs and QALYs showed that PI monotherapy was associated with significant cost savings and was marginally less effective; PI monotherapy was cost effective at accepted cost-effectiveness thresholds in all but one scenario analysis. Conclusions Under most assumptions, PI monotherapy appears to be a cost-effective treatment strategy compared with OT for HIV-infected patients who have achieved sustained virological suppression

The clinical effectiveness and cost-effectiveness of cetuximab (review of technology appraisal no. 176) and panitumumab (partial review of technology appraisal no. 240) for previously untreated metastatic colorectal cancer: a systematic review and economic evaluation.

Colorectal cancer is the fourth most commonly diagnosed cancer in the UK after breast, lung and prostate cancer. People with metastatic disease who are sufficiently fit are usually treated with active chemotherapy as first- or second-line therapy. Targeted agents are available, including the antiepidermal growth factor receptor (EGFR) agents cetuximab (Erbitux(®), Merck Serono UK Ltd, Feltham, UK) and panitumumab (Vecitibix(®), Amgen UK Ltd, Cambridge, UK).This report is freely available online. Click on the Additional Link above to access the full-text via the publisher's site

Immunosuppressive therapy for kidney transplantation in adults: a systematic review and economic model.

End-stage renal disease is a long-term irreversible decline in kidney function requiring renal replacement therapy: kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation, followed by immunosuppressive therapy (induction and maintenance therapy) to reduce the risk of kidney rejection and prolong graft survival.This article is freely available. Click on the 'Additional Link' above to access the full-text