C McLeod

Cytochrome P450 testing for prescribing antipsychotics in adults with schizophrenia: systematic review and meta-analyses.

There is wide variability in the response of individuals to standard doses of antipsychotic drugs. It has been suggested that this may be partly explained by differences in the cytochrome P450 (CYP450) enzyme system responsible for metabolizing the drugs. We conducted a systematic review and meta-analyses to consider whether testing for CYP450 single nucleotide polymorphisms in adults starting antipsychotic treatment for schizophrenia predicts and leads to improvements in clinical outcomes. High analytic validity in terms of sensitivity and specificity was seen in studies reporting P450 testing. However, there was limited evidence of the role of CYP2D6 polymorphisms in antipsychotic efficacy, although there was an association between CYP2D6 genotype and extrapyramidal adverse effects. No studies reported on the prospective use of CYP2D6 genotyping tests in clinical practice. In conclusion, evidence of clinical validity and utility of CYP2D6 testing in patients being prescribed antipsychotics is lacking, and thus, routine pharmacogenetic testing prior to antipsychotic prescription cannot be supported at present. Further research is required to improve the evidence base and to generate data on clinical validity and clinical utility.

The clinical effectiveness and cost-effectiveness of testing for cytochrome P450 polymorphisms in patients with schizophrenia treated with antipsychotics: a systematic review and economic evaluation

OBJECTIVE To determine whether testing for cytochrome P450 (CYP) polymorphisms in adults entering antipsychotic treatment for schizophrenia leads to improvement in outcomes, is useful in medical, personal or public health decision-making, and is a cost-effective use of health-care resources. DATA SOURCES The following electronic databases were searched for relevant published literature: Cochrane Controlled Trials Register, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effectiveness, EMBASE, Health Technology Assessment database, ISI Web of Knowledge, MEDLINE, PsycINFO, NHS Economic Evaluation Database, Health Economic Evaluation Database, Cost-effectiveness Analysis (CEA) Registry and the Centre for Health Economics website. In addition, publicly available information on various genotyping tests was sought from the internet and advisory panel members. REVIEW METHODS A systematic review of analytical validity, clinical validity and clinical utility of CYP testing was undertaken. Data were extracted into structured tables and narratively discussed, and meta-analysis was undertaken when possible. A review of economic evaluations of CYP testing in psychiatry and a review of economic models related to schizophrenia were also carried out. RESULTS For analytical validity, 46 studies of a range of different genotyping tests for 11 different CYP polymorphisms (most commonly CYP2D6) were included. Sensitivity and specificity were high (99-100%). For clinical validity, 51 studies were found. In patients tested for CYP2D6, an association between genotype and tardive dyskinesia (including Abnormal Involuntary Movement Scale scores) was found. The only other significant finding linked the CYP2D6 genotype to parkinsonism. One small unpublished study met the inclusion criteria for clinical utility. One economic evaluation assessing the costs and benefits of CYP testing for prescribing antidepressants and 28 economic models of schizophrenia were identified; none was suitable for developing a model to examine the cost-effectiveness of CYP testing. CONCLUSIONS Tests for determining genotypes appear to be accurate although not all aspects of analytical validity were reported. Given the absence of convincing evidence from clinical validity studies, the lack of clinical utility and economic studies, and the unsuitability of published schizophrenia models, no model was developed; instead key features and data requirements for economic modelling are presented. Recommendations for future research cover both aspects of research quality and data that will be required to inform the development of future economic models.

Cetuximab for Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck: A NICE Single Technology Appraisal

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of cetuximab (Merck Serono) to submit evidence for the clinical and cost effectiveness of cetuximab in combination with platinumbased chemotherapy (CTX) for the treatment of patients with recurrent and/or metastatic squamous cell cancer of the head and neck (SCCHN) according to the Institute’s Single Technology Appraisal (STA) process. The Liverpool Reviews and Implementation Group at the University of Liverpool was commissioned to act as the Evidence Review Group (ERG).This article summarizes the ERGs review of the evidence submitted by the manufacturer.Asummary of theAppraisal Committee (AC) decision is provided.The ERG reviewed the clinical evidence in accordance with the decision problem defined by NICE. The analysis of the submitted model assessed the appropriateness of the manufacturers approach to modelling the decision problem, the reliability of model implementation and the extent of conformity to published standards and prevailing norms of practice within the health economics modelling community. Particular attention was paid to issues likely to impact substantially on the base-case cost-effectiveness results.Clinical-effectiveness evidence was derived from a single randomized controlled trial (RCT). Results presented for clinical outcomes were strongly supportive of benefits resulting from the use of cetuximab. Cetuximab + platinum-based CTX with 5 fluorouracil (5-FU) extended median overall survival (OS) from 7.4 months in the CTX group to 10.1 months in the cetuximab +CTX group. Median progression-free survival rose from 3.3months to 5.6 months, best overall response to therapy increased from 19.5% to 35.6%, disease control rate rose from60%to 81.1%andmedian time to treatment failure was 4.8 months compared with 3.0 months.Exploratory subgroup analyses indicated significant OS benefits in 11 of 16 pre-planned analyses.The ERG identified a number of issues relating to the clinical-effectiveness results: consideration was limited to first-line use of cetuximab; patients in the trial were younger and fitter than those presenting in UK clinical practice; there was no evidence of survival advantage for patients with metastatic disease; there was no evidence of effectiveness in patients not cetuximabnaive; and the quality-of-life data were poor.The submitted incremental cost-effectiveness ratio was considerably above the NICE threshold. The ERG questioned the submitted economic model on a number of grounds: the rationale for creating an economic model rather than direct analysis of trial data; the use of Weibull functions for survival models; inaccurate CTX costs; selection of health state utilities; inaccurate unit costs; and lack of mid-cycle correction. After amending the model, the ERG considered the use of cetuximab to be not cost effective for NICE at any price.The AC concluded that cetuximab in combination with platinum-based CTX should not be recommended for the treatment of patients with recurrent and/or metastatic SCCHN. Patients already receiving this treatment for this indication should have the option to continue treatment until they and their clinician consider it appropriate to stop. This was the first appraisal to consider the end-of-life medicines criteria introduced by NICE in January 2009.

Cetuximab for the treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of cetuximab for recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) based upon a review of the manufacturers submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The submissions evidence came from a single reasonably high-quality randomised controlled trial (RCT) [EXTREME (Erbitux in First-Line Treatment of Recurrent or Metastatic Head and Neck Cancer); n = 442] comparing cetuximab plus chemotherapy (CTX) with CTX alone. Cetuximab plus CTX had significant effects compared with CTX alone on the primary outcome of overall survival (10.1 versus 7.4 months respectively) and the secondary outcomes of progression-free survival (PFS) (5.6 versus 3.3 months), best overall response to therapy (35.6% versus 19.5%), disease control rate (81.1% versus 60%) and time-to-treatment failure (4.8 versus 3.0 months), but not on duration of response (5.6 months versus 4.7 months). No safety issues with cetuximab arose beyond those already previously documented. The manufacturer developed a two-arm state-transition Markov model to evaluate the cost-effectiveness of cetuximab plus CTX versus CTX alone, using clinical data from the EXTREME trial. The ERG recalculated the base-case cost-effectiveness results taking changes in parameters and assumptions into account. Subgroup and threshold analyses were also explored. The manufacturer reported an incremental cost-effectiveness ratio (ICER) of 121,367 pounds per quality-adjusted life-year (QALY) gained and an incremental cost per life-year gained of 92,226 pounds. Univariate sensitivity analysis showed that varying the cost of day-case infusion and the utility values in the stable/response health state of the cetuximab plus CTX arm had the greatest impact on the ICER. Probabilistic sensitivity analysis illustrated that cetuximab plus CTX is unlikely to be cost-effective for patients with recurrent and/or metastatic SCCHN, even at what would usually be considered very high levels of willingness to pay for an additional QALY. With regard to the economic model the appropriateness and reliability of parametric survival projection beyond the duration of trial data could not be fully explored because of lack of information. The ERG also questioned the appropriateness of economic modelling in this STA as evidence is available only from a single RCT. In conclusion, the ERG considers that patients with metastatic SCCHN were not shown to receive a significant survival benefit from cetuximab plus CTX compared with CTX alone and that even setting a lower price for cetuximab would not strengthen the manufacturers case for cost-effectiveness.

Rituximab for the first-line treatment of stage III/IV follicular non-Hodgkin's lymphoma.

This paper presents a summary of the evidence review group (ERG) report into the clinical and cost-effectiveness of rituximab for the first-line treatment of stage III/IV follicular non-Hodgkins lymphoma (FNHL) based upon the manufacturers submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The manufacturers scope restricts the intervention to rituximab in combination with CVP (cyclophosphamide, vincristine and prednisolone) (R-CVP); the only comparator used was CVP alone. The evidence from the one included randomised controlled trial (RCT) suggests that the addition of rituximab to a CVP chemotherapy regimen has a positive effect on the outcomes of time to treatment failure, disease progression, overall tumour response, duration of response and time to new lymphoma treatment in patients with stage III/IV FNHL compared with CVP alone. Adverse events were comparable between the two arms. This study was confirmed as the only relevant RCT. The economic analyses provided by the manufacturer were modelled using a three-state Markov model with with the health states being defined as progression-free survival (PFS), progressed (in which patients have relapsed) and death (which is an absorbing state). The model generated results for a cohort of patients with an initial age of 53 and makes no distinction between men and women. The model is basic in design, with several serious design flaws and key parameter values that are probably incompatible. Attempting to rectify the identified errors and limitations of the model did not increase the incremental cost-effectiveness ratio (ICER) above 30,000 pounds. Although the cost-effectiveness results obtained appear to be compelling in support of R-CVP compared with CVP for the trial population the results may not be so convincing for a more representative population. The results of the ERG analysis on the impact of age suggest that ICERs increase steadily with age, as the proportion of PFS that can be converted to overall survival (OS) is diminished by rising mortality rates in the general population. For the most extreme scenario (no OS gain) the ICER appears to remain below 30,000 pounds per QALY gained. On balance the evidence indicates that R-CVP is more cost-effective than CVP. The guidance issued by NICE in July 2006 as a result of the STA states that rituximab within its licensed indication (in combination with cyclophosphamide, vincristine and prednisolone) is recommended as an option for the treatment of symptomatic stage III/IV follicular non-Hodgkins lymphoma in previously untreated patients.

Erlotinib for the treatment of relapsed non-small cell lung cancer.

This paper presents a summary of the evidence review group (ERG) report into the clinical and cost-effectiveness of erlotinib for the treatment of relapsed non-small cell lung cancer (NSCLC), according to its licensed indication, based upon the evidence submission from Roche Products to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The submitted clinical evidence includes one randomised controlled trial (RCT) (BR21) investigating the effect of erlotinib versus placebo, which demonstrates that erlotinib significantly increases median overall survival, progression-free survival and response rate compared with placebo. The majority of patients in the trial experienced non-haematological drug-related adverse effects. Currently there are no trials that directly compare erlotinib with any other second-line chemotherapy agent. For the purposes of indirect comparison, the manufacturers submission provides a narrative discussion of data from 11 RCTs investigating the use of docetaxel. From these data the manufacturer concludes that erlotinib has similar clinical efficacy levels to docetaxel but results in fewer serious haematological adverse events; however, it is difficult to compare the results of BR21 with those of the docetaxel trials or with current UK clinical practice because, for example, the BR21 patient population is younger than that expected to present in UK clinical practice and almost half of the BR21 participants received erlotinib as third-line chemotherapy, with third-line chemotherapy being rare in the UK. The manufacturers submission included a three-state model comparing erlotinib with docetaxel, reporting an incremental cost-effectiveness ratio (ICER) of 1764 pounds per quality-adjusted life-year (QALY) gained for erlotinib compared with docetaxel. Rerunning the manufacturers economic model with varied parameters and assumptions increases the ICER to in excess of 52,000 pounds per QALY gained. There is still a large amount of unquantifiable uncertainty in the model and it is unlikely that erlotinib could be considered to be cost-effective compared with docetaxel at a willingness to pay of 30,000 pounds and there may even be the potential for docetaxel to dominate erlotinib. Because of the limitations of the indirect analysis undertaken by the manufacturer and the subsequent economic modelling exercise there is a need for a head-to-head trial comparing erlotinib with docetaxel. The guidance issued by NICE in February 2007 as a result of the STA states that erlotinib is not recommended for the treatment of locally advanced or metastatic NSCLC.

Deferasirox for the treatment of iron overload associated with regular blood transfusions (transfusional haemosiderosis) in patients suffering with chronic anaemia: a systematic review and economic evaluation

OBJECTIVES To assess the clinical effectiveness and cost-effectiveness of deferasirox for the treatment of iron overload associated with regular blood transfusions in patients with chronic anaemia such as beta-thalassaemia major (beta-TM) and sickle cell disease (SCD). DATA SOURCES Electronic databases were searched up to March 2007. REVIEW METHODS Methods followed accepted procedures for conducting and reporting systematic reviews and economic evaluations. RESULTS A total of 14 randomised controlled trials (RCTs) involving a study population of 1480 (ranging from 13 to 586) met the inclusion criteria. There was a high degree of heterogeneity between trials in terms of trial design and outcome reporting. As such it was only possible to meta-analyse serum ferritin data from six trials making comparisons between deferiprone and DFO and combination therapy and DFO. Only one of the results was statistically significant, favouring combination therapy over DFO alone for serum ferritin at 12 months. How this translates into iron loading in organs such as the heart is unclear, nor was it possible to determine the long-term benefits of chelation therapy. Eight full economic evaluations (one full paper; seven abstracts) were included in the review. The results were generally consistent and appear to demonstrate the cost-effectiveness of deferasirox compared with DFO for the treatment of iron overload in a number of different patient populations and study locations. However, a number of assumptions and, in the case of the long-term studies, extrapolation from short-term RCT data were required, which render the results highly speculative at best. Because of the paucity of long-term data we developed a simple, short-term (1 year) model to assess the costs and benefits of deferasirox, deferiprone and DFO in patients with beta-TM and SCD from an NHS perspective. A number of assumptions were required to generate results and, as such, they should be interpreted as indicative rather than factual. Our model suggests that deferasirox may be a cost-effective strategy compared with DFO, at a cost per quality-adjusted life-year (QALY) below 30,000 pounds per year, for patients with beta-TM and SCD. However, this is highly dependent upon the age of the patient and the use and benefits of balloon infusers to administer DFO. Deferasirox compared with deferiprone is likely to be cost-effective only for young children. Furthermore, if deferiprone is proven to offer the same health benefits as deferasirox, the latter will not be cost-effective for any patient compared with deferiprone. CONCLUSIONS In the short term there is little clinical difference between any of the three chelators in terms of removing iron from the blood and liver. Deferasirox may be cost-effective compared with DFO in patients with beta-TM and SCD, but it is unlikely to be cost-effective compared with deferiprone. Elucidating the long-term benefits of chelation therapy, including issues of adverse events and adherence, should be the primary focus for future research. Future work should aim for consistency and transparency in reporting study design and results to aid decision-making when making comparisons across trials.

Prasugrel for the treatment of acute coronary artery syndromes with percutaneous coronary intervention.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of prasugrel for the treatment of coronary artery syndromes with percutaneous coronary intervention, based upon the evidence submission from Eli Lilly to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The submitted clinical evidence was based on a phase III double-blind, double-dummy randomised controlled trial which compared the use of prasugrel with clopidogrel. The primary clinical outcome measure was a composite end point of death from cardiovascular causes, non-fatal myocardial infarction (MI) or non-fatal stroke at 15 months. Secondary outcomes included the primary end point at 30 days and 90 days; a composite end point of death from cardiovascular causes, non-fatal MI or urgent target vessel revascularisation; a composite end point of death from cardiovascular causes, non-fatal MI, non-fatal stroke or rehospitalisation due to a cardiac ischaemic event; and stent thrombosis. For the overall trial cohort during the 15 month follow-up period, the results of the trial demonstrated a statistically significant benefit of prasugrel compared with clopidogrel on the primary outcome. The efficacy difference between treatment groups was, in the main, due to a statistically significant lower incidence of non-fatal MIs in the prasugrel group than in the clopidogrel group. No statistically significant differences were found for death from cardiovascular causes or non-fatal stroke. For the fully licensed and target populations, there was a statistically significant lower incidence of non-fatal MIs in the prasugrel group than in the clopidogrel group; there was no statistically significant difference in bleeding rates. The ERG recalculated the base-case cost-effectiveness results taking changes in parameters and assumptions into account: for example, revised drug costs, mid-cycle correction, amended relative risk mortality. Subgroup and threshold analyses were also explored by the ERG. For the fully licensed population (i.e. excluding patients with prior stroke or TIA), the manufacturer reported an incremental cost-effectiveness ratio (ICER) of 159,358 pounds per quality-adjusted life-year (QALY) gained at 12 months and an ICER of 3,220 pounds per QALY gained at 40 years. Considering the 15-month clinical trial data available for the fully licensed and target populations and current practice in England and Wales, the evidence was considered insufficient to support the conclusion that prasugrel is clinically more effective than clopidogrel or vice versa. Assuming that there is no evidence to distinguish between prasugrel and clopidogrel in terms of clinical effectiveness in the short term for this population, equipoise between prasugrel and clopidogrel at year 1 is achieved by a 20% reduction in the acquisition cost of prasugrel (approximately 120 pounds per patient). At the time of writing, the guidance/has not yet been published by NICE.

Pemetrexed for the maintenance treatment of locally advanced or metastatic non-small cell lung cancer.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of pemetrexed for the maintenance treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC), in accordance with the licensed indication, based upon the evidence submission from the manufacturer (Eli Lilly) to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The primary clinical outcome measure was progression free survival (PFS). Secondary outcomes included overall survival (OS), time to worsening of symptoms, objective tumour response rate, adverse events and changes in lung cancer symptom scale. Data for two populations were presented: patients with non-squamous NSCLC histology and patients with adenocarcinoma histology. The clinical evidence was derived from a double-blind, placebo-controlled randomised controlled trial (RCT), the JMEN trial. The trial compared the use of pemetrexed + best supportive care (BSC ) as maintenance therapy, with placebo + BSC in patients with NSCLC (n = 663) who had received four cycles of platinum-based chemotherapy (CTX) and whose disease had not progressed. In the licensed population (patients with non-squamous histology), the trial demonstrated greater median PFS for patients treated with pemetrexed than for patients in the placebo arm [4.5 vs 2.6 months; hazard ratio (HR) 0.44; 95% confidence interval (CI) 0.36 to 0.55, p < 0.00001]. Median OS was also greater for the pemetrexed- treated patients (15.5 vs 10.3 months; HR 0.70; 95% CI 0.56 to 0.88, p = 0.002). In addition, tumour response and disease control rates were statistically significantly greater for patients who received pemetrexed. Patient survival rates at 1 year and 2 years were higher in the pemetrexed arm. The incremental cost-effectiveness ratios (ICERs) estimated by the manufacturers model were 33,732 pounds per quality adjusted life-year (QALY) for the licensed nonsquamous population, and 39,364 pounds per QALY for the adenocarcinoma subgroup. Both of these ICERs were above the standard NICE willingness-to-pay range (20,000 pounds-30,000 pounds per QALY). The manufacturer also presented a case for pemetrexed to be considered as an end of life treatment. The ERG identified a number of problems in the economic model presented by the manufacturer; after correction, the base case ICER was re-estimated as 51,192 pounds per QALY gained and likely to exceed NICEs willingness-to-pay thresholds. Following a revised economic analysis submitted by the manufacturer, the AC accepted that an ICER of 47,000 pounds per QALY gained was most plausible. The AC also considered that maintenance treatment with pemetrexed fulfilled the end of life criteria.The guidance issued by NICE, on 20 June 20 2010, in TA190 as a result of the STA states that: People who have received pemetrexed in combination with cisplatin as first-line chemotherapy cannot receive pemetrexed maintenance treatment. 1.1 Pemetrexed is recommended as an option for the maintenance treatment of people with locally advanced or metastatic non-small-cell lung cancer other than predominantly squamous cell histology if disease has not progressed immediately following platinum-based chemotherapy in combination with gemcitabine, paclitaxel or docetaxel.

Best supportive care in lung cancer trials is inadequately described: a systematic review

The objective of the paper was to identify and discuss clinical terms associated with the availability and delivery of best supportive care for patients with lung cancer in randomised controlled clinical trials. Systematic review was carried out of relevant studies without language restrictions identified through Medline, EMBASE, Science Citation Index (Web of Science and ISI Proceedings) and Cochrane Library. Reference lists of retrieved articles were also searched to identify further studies. Articles describing randomised controlled trials or systematic reviews with a comparator arm of best supportive care for patients with lung cancer were studied. Definitions of best supportive care and elements of best supportive care were reported. Included clinical studies (n = 40) did not adequately describe or outline either the components or the delivery of best supportive care for patients in lung cancer trials. None of the identified studies provided a clear definition of a patient pathway in relation to best supportive care, or a clear list of components. Clinical studies are being conducted without a clear definition of the best supportive care provided in the comparator arms of trials. Inadequate definitions mean that all direct and indirect comparisons in trials comparing active treatments with best supportive care must be interpreted with caution.