Cladribine Tablets for the First-Line Treatment of Relapsing-Remitting Multiple Sclerosis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of the single technology appraisal process, the National Institute for Health and Care Excellence invited Merck to submit evidence for the clinical and cost effectiveness of cladribine tablets (cladribine) for the treatment of relapsing-remitting multiple sclerosis (RRMS). Rapidly evolving severe (RES) and sub-optimally treated (SOT) RRMS were specified by the National Institute for Health and Care Excellence as subgroups of interest. The Liverpool Reviews and Implementation Group at the University of Liverpool was the Evidence Review Group. This article summarises the Evidence Review Group's review of the company's evidence submission for cladribine and the Appraisal Committee's final decision. The final scope issued by the National Institute for Health and Care Excellence listed the following disease-modifying treatments as comparators: alemtuzumab, daclizumab, fingolimod and natalizumab. At the time of the company submission, a licence was anticipated for low-dose cladribine. The main clinical evidence (the CLARITY trial) in the company submission focused on the efficacy of low-dose cladribine vs. placebo. The CLARITY trial showed a statistically significant reduction in relapse rate for cladribine in the RES-RRMS subgroup (n = 50) but not in the SOT-RRMS subgroup (n = 19). Cladribine showed a numerical, but not a statistically significant, advantage in delaying disability progression at 6 months in the RES-RRMS subgroup. Disability progression benefits could not be estimated for those in the SOT-RRMS subgroup because of few events. The Evidence Review Group's main concern regarding the clinical evidence was the small sample size of the subgroups. To compare the effectiveness of cladribine to other disease-modifying treatments, the company conducted network meta-analyses, which showed cladribine and its comparators to be equally effective. The Evidence Review Group considered the results of the disease-modifying treatments to be unreliable because few trials were in the network. The company's cost-effectiveness evidence showed cladribine to be cheaper and more effective than other disease-modifying treatments in the RES-RRMS arm and the SOT-RRMS arm. The results were most sensitive to treatment effect on disability progression at 6 months. The Evidence Review Group was concerned that there was insufficient evidence to conclude that cladribine was superior to placebo in delaying disability progression. The Evidence Review Group amended the company's economic model to allow alternative estimates for the treatment effect of cladribine and its comparators on relapse rate and disability progression at 6 months. The Evidence Review Group made other changes to the company model. After implementing all the amendments, cladribine remained cost effective in the RES-RRMS and SOT-RRMS subgroups. The Appraisal Committee recognised the uncertainty in the available data but concluded that cladribine could be considered a cost-effective use of National Health Service resources.

Pegylated Liposomal Irinotecan Hydrochloride Trihydrate for Treating Pancreatic Cancer After Gemcitabine: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Shire Pharmaceuticals) of pegylated liposomal irinotecan hydrochloride trihydrate (liposomal irinotecan) to submit clinical and cost-effectiveness evidence for its use in combination with 5-fluorouracil (5-FU) and folic acid/leucovorin (LV) for treating patients with pancreatic cancer following prior treatment with gemcitabine as part of the institute's Single Technology Appraisal process. The Liverpool Reviews and Implementation Group at the University of Liverpool was commissioned to act as the Evidence Review Group (ERG). This article presents a summary of the company's evidence, the ERG review and the resulting NICE guidance (TA440), issued on 26 April 2017. Clinical evidence for liposomal irinotecan + 5-FU/LV versus 5-FU/LV was derived from 236 patients with metastatic pancreatic cancer in the multinational, open-label, randomised controlled NAPOLI-1 trial. Results from analyses of progression-free survival and overall survival showed statistically significant improvements for patients treated with liposomal irinotecan + 5-FU/LV compared with those treated with 5-FU/LV. However, 5-FU/LV alone is rarely used in National Health Service clinical practice for patients with metastatic pancreatic cancer previously treated with gemcitabine. The company, ERG and Appraisal Committee (AC) all agreed that oxaliplatin + 5-FU/LV is the most commonly used treatment. Oxaliplatin + 5-FU/LV was compared with 5-FU/LV in two trials identified by the company. However, the company and the ERG both considered attempts to compare the efficacy of liposomal irinotecan + 5-FU/LV with oxaliplatin + 5-FU/LV to be methodologically flawed; not only was there heterogeneity between trials and their populations but also the proportional hazards assumption required to conduct a robust indirect treatment comparison (ITC) was violated. Nonetheless, data derived from an ITC were used to inform the company's economic model. Using the discounted patient access scheme price for liposomal irinotecan + 5-FU/LV, the company reported an incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY) gained of £54,412 for the comparison with oxaliplatin + 5-FU/LV. The ERG considered that the company's base-case cost-effectiveness results for the comparison of liposomal irinotecan + 5-FU/LV versus oxaliplatin + 5-FU/LV were underestimates and should be interpreted with extreme caution. Following implementation of a number of model amendments, the ERG's modified exploratory ICER for the comparison of liposomal irinotecan + 5-FU/LV versus oxaliplatin + 5-FU/LV was £106,898 per QALY gained. The AC accepted the majority of the ERG's amendments to the model, and also highlighted that the total QALYs for oxaliplatin + 5-FU/LV were lower than for 5-FU/LV in the company's model, which the AC considered to be clinically implausible. The AC therefore considered results from exploratory analyses, undertaken by the ERG, which included altering the QALY difference between liposomal irinotecan + 5-FU/LV and oxaliplatin + 5-FU/LV by ± 10%. These analyses resulted in ICERs for the comparison of liposomal irinotecan + 5-FU/LV versus oxaliplatin + 5-FU/LV of between £201,019 per QALY gained to liposomal irinotecan + 5-FU/LV being dominated by oxaliplatin + 5-FU/LV. Therefore, despite uncertainty around the clinical-effectiveness evidence and cost-effectiveness results, the AC was confident that the ICER was in excess of £50,000 per QALY gained. The final guidance issued by NICE is that liposomal irinotecan + 5-FU/LV is not recommended within its marketing authorisation for treating metastatic adenocarcinoma of the pancreas in adults whose disease has progressed after gemcitabine-based therapy.

Prasugrel (Efient®) with percutaneous coronary intervention for treating acute coronary syndromes (review of TA182): systematic review and economic analysis.

BACKGROUND: Acute coronary syndromes (ACSs) are life-threatening conditions associated with acute myocardial ischaemia. There are three main types of ACS: ST segment elevation myocardial infarction (STEMI), non-ST segment elevation myocardial infarction (NSTEMI) and unstable angina (UA). One treatment for ACS is percutaneous coronary intervention (PCI) plus adjunctive treatment with antiplatelet drugs. Dual therapy antiplatelet treatment [aspirin plus either prasugrel (Efient(®), Daiichi Sankyo Company Ltd UK/Eli Lilly and Company Ltd), clopidogrel or ticagrelor (Brilique(®), AstraZeneca)] is standard in UK clinical practice. Prasugrel is the focus of this review. OBJECTIVES: The remit is to appraise the clinical effectiveness and cost-effectiveness of prasugrel within its licensed indication for the treatment of ACS with PCI and is a review of National Institute for Health and Care Excellence technology appraisal TA182. DATA SOURCES: Four electronic databases (MEDLINE, EMBASE, The Cochrane Library, PubMed) were searched from database inception to June 2013 for randomised controlled trials (RCTs) and to August 2013 for economic evaluations comparing prasugrel with clopidogrel or ticagrelor in ACS patients undergoing PCI. METHODS: Clinical outcomes included non-fatal and fatal cardiovascular (CV) events, adverse effects of treatment and health-related quality of life (HRQoL). Cost-effectiveness outcomes included incremental cost per life-year gained and incremental cost per quality-adjusted life-year (QALY) gained. An independent economic model assessed four mutually exclusive subgroups: ACS patients treated with PCI for STEMI and with and without diabetes mellitus and ACS patients treated with PCI for UA or NSTEMI and with and without diabetes mellitus. RESULTS: No new RCTs were identified beyond that reported in TA182. TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel Thrombolysis in Myocardial Infarction 38) compared prasugrel with clopidogrel in ACS patients scheduled for PCI. No relevant economic evaluations were identified. Our analyses focused on a key subgroup of patients: those aged < 75 years who weighed > 60 kg (no previous stroke or transient ischaemic attack). For the primary composite end point (death from CV causes, non-fatal myocardial infarction or non-fatal stroke) statistically significantly fewer events occurred in the prasugrel arm (8.3%) than in the clopidogrel arm (11%). No statistically significant difference in major bleeding events was noted. However, there was a significant difference in favour of clopidogrel when major and minor bleeding events were combined (3.0 vs. 3.9%). No conclusions could be drawn regarding HRQoL. The results of sensitivity analyses confirmed that it is likely that, for all four ACS subgroups, within 5-10 years prasugrel is a cost-effective treatment option compared with clopidogrel at a willingness-to-pay threshold of £20,000 to £30,000 per QALY gained. At the full 40-year time horizon, all estimates are < £10,000 per QALY gained. LIMITATIONS: Lack of data precluded a clinical comparison of prasugrel with ticagrelor; the comparative effectiveness of prasugrel compared with ticagrelor therefore remains unknown. The long-term modelling exercise is vulnerable to major assumptions about the continuation of early health outcome gains. CONCLUSION: A key strength of the review is that it demonstrates the cost-effectiveness of prasugrel compared with clopidogrel using the generic price of clopidogrel. Although the report demonstrates the cost-effectiveness of prasugrel compared with clopidogrel at a threshold of £20,000 to £30,000 per QALY gained, the long-term modelling is vulnerable to major assumptions regarding long-term gains. Lack of data precluded a clinical comparison of prasugrel with ticagrelor; the comparative effectiveness of prasugrel compared with ticagrelor therefore remains unknown. Well-audited data are needed from a long-term UK clinical registry on defined ACS patient groups treated with PCI who receive prasugrel, ticagrelor and clopidogrel. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013005047. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Utility and value of a medicines information service provided by pharmacists: a survey of health professionals.

OBJECTIVES: many health professionals lack the time and skills to search for and appraise information on medicines. A solution might be to use others skilled in evidence appraisal, who make recommendations or provide information tailored to patients' needs. The objectives of this study were to assess how advice provided to health professionals by the northwest of England regional medicines information centre is used, whether it is useful for patient care and to measure satisfaction with the service. METHODS: a questionnaire was designed and sent to health professionals who contacted the centre between September 2008 and March 2009. Enquirers contacting the centre more than once were sent a questionnaire only in response to their first enquiry during the study period. Non-responders were sent a reminder. KEY FINDINGS: questionnaires were sent to 672 enquirers; 68% were returned. Nearly all respondents used the advice provided. Of the 430 respondents who provided data on how they used the information, 81% used it to manage a current patient and 29% to plan the care of future patients; nearly all considered it useful. Where data were given (n = 366), half used it to check if current or proposed management was appropriate, 45% to make changes to therapy and 35% to advise another health professional. In addition to patient care, one-quarter (n = 105/430) of respondents used the information for continuing professional development and 16% (n = 69/430) for training or teaching. CONCLUSIONS: health professionals value the enquiry-answering service and use the advice provided for patient care, continuing professional development and educating patients and other health professionals. The service is responsive, supporting the care of patients needing immediate and future management.