Reduced need for surgery in severe nasal polyposis with mepolizumab: Randomized trial.
01 Oct 2017-The Journal of Allergy and Clinical Immunology (Elsevier)-Vol. 140, Iss: 4, pp 1024-1031
TL;DR: In patients with recurrent nasal polyposis receiving topical corticosteroids who required surgery, mepolizumab treatment led to a greater reduction in the need for surgery and a greater improvement in symptoms than placebo.
Abstract: Background Patients with eosinophilic nasal polyposis frequently require surgery, and recurrence rates are high. Objective We sought to assess the efficacy and safety of mepolizumab versus placebo for severe bilateral nasal polyposis. Methods This randomized, double-blind, placebo-controlled trial recruited patients aged 18 to 70 years with recurrent nasal polyposis requiring surgery. Patients received 750 mg of intravenous mepolizumab or placebo every 4 weeks for a total of 6 doses in addition to daily topical corticosteroid treatment. The primary end point was the number of patients no longer requiring surgery at Week 25 based on a composite end point of endoscopic nasal polyp score and nasal polyposis severity visual analog scale (VAS) score. Secondary end points included change in nasal polyposis severity VAS score, endoscopic nasal polyp score, improvement in individual VAS symptoms (rhinorrhea, mucus in throat, nasal blockage, and sense of smell), patient-reported outcomes, and safety. Results One hundred five patients received mepolizumab (n = 54) or placebo (n = 51). A significantly greater proportion of patients in the mepolizumab group compared with the placebo group no longer required surgery at Week 25 (16 [30%] vs 5 [10%], respectively; P = .006). There was a significant improvement in nasal polyposis severity VAS score, endoscopic nasal polyp score, all individual VAS symptom scores, and Sino-Nasal Outcome Test patient-reported outcome score in the mepolizumab compared with placebo groups. Mepolizumab's safety profile was comparable with that of placebo. Conclusion In patients with recurrent nasal polyposis receiving topical corticosteroids who required surgery, mepolizumab treatment led to a greater reduction in the need for surgery and a greater improvement in symptoms than placebo.
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University of Amsterdam1, Ghent University2, University of Chicago3, University of Pennsylvania4, Lund University5, Auckland City Hospital6, University of Antwerp7, University of New South Wales8, Katholieke Universiteit Leuven9, Guy's and St Thomas' NHS Foundation Trust10, Queen's University11, University of Zagreb12, Northwestern University13, Medical University of Łódź14, University of Aberdeen15, Medical University of South Carolina16, University of North Carolina at Chapel Hill17, University of Southampton18, University of São Paulo19, National University of Singapore20, Flinders University21
TL;DR: The European Position Paper on Rhinosinusitis and Nasal Polyps 2020 is the update of similar evidence based position papers published in 2005 and 2007 and 2012 and addresses areas not extensively covered in EPOS2012 such as paediatric CRS and sinus surgery.
Abstract: The European Position Paper on Rhinosinusitis and Nasal Polyps 2020 is the update of similar evidence based position papers published in 2005 and 2007 and 2012. The core objective of the EPOS2020 guideline is to provide revised, up-to-date and clear evidence-based recommendations and integrated care pathways in ARS and CRS. EPOS2020 provides an update on the literature published and studies undertaken in the eight years since the EPOS2012 position paper was published and addresses areas not extensively covered in EPOS2012 such as paediatric CRS and sinus surgery. EPOS2020 also involves new stakeholders, including pharmacists and patients, and addresses new target users who have become more involved in the management and treatment of rhinosinusitis since the publication of the last EPOS document, including pharmacists, nurses, specialised care givers and indeed patients themselves, who employ increasing self-management of their condition using over the counter treatments. The document provides suggestions for future research in this area and offers updated guidance for definitions and outcome measurements in research in different settings. EPOS2020 contains chapters on definitions and classification where we have defined a large number of terms and indicated preferred terms. A new classification of CRS into primary and secondary CRS and further division into localized and diffuse disease, based on anatomic distribution is proposed. There are extensive chapters on epidemiology and predisposing factors, inflammatory mechanisms, (differential) diagnosis of facial pain, allergic rhinitis, genetics, cystic fibrosis, aspirin exacerbated respiratory disease, immunodeficiencies, allergic fungal rhinosinusitis and the relationship between upper and lower airways. The chapters on paediatric acute and chronic rhinosinusitis are totally rewritten. All available evidence for the management of acute rhinosinusitis and chronic rhinosinusitis with or without nasal polyps in adults and children is systematically reviewed and integrated care pathways based on the evidence are proposed. Despite considerable increases in the amount of quality publications in recent years, a large number of practical clinical questions remain. It was agreed that the best way to address these was to conduct a Delphi exercise . The results have been integrated into the respective sections. Last but not least, advice for patients and pharmacists and a new list of research needs are included. The full document can be downloaded for free on the website of this journal: http://www.rhinologyjournal.com.
2,853 citations
TL;DR: To elucidate the efficacy, safety, and patient characteristics of responsiveness to mepolizumab (a humanized monoclonal antibody against interleukin 5), a large number of patients with severe, eosinophilic asthma were enrolled in 81 multinational centers.
Abstract: ID Pavord, S Korn, P Howarth. Lancet. 2012;380(9842):651–659
To elucidate the efficacy, safety, and patient characteristics of responsiveness to mepolizumab (a humanized monoclonal antibody against interleukin 5). Previous small, proof-of-concept studies in subjects with severe, eosinophilic asthma revealed that mepolizumab decreased exacerbation rates.
From 81 multinational centers, 621 pa-tients were enrolled. Major inclusion criteria included: age 12 to 74 years, asthma diagnosis with objective measures, ≥2 asthma exacerbations requiring oral corticosteroids in the last year, refractory asthma as defined by the American …
387 citations
University of Utah1, University of Colorado Denver2, Oregon Health & Science University3, Harvard University4, University of California, San Diego5, University of Texas Health Science Center at Houston6, Medical College of Wisconsin7, Medical University of South Carolina8, Northwestern University9, Emory University10, University of Pennsylvania11, University of São Paulo12, Karolinska Institutet13, Ghent University14, Sun Yat-sen University15, University of Chicago16, Rush University Medical Center17, University of Barcelona18, University of California, Los Angeles19, Vanderbilt University20, University of Arizona21, University of Kansas22, Université de Montréal23, University of Auckland24, Rutgers University25, University of Amsterdam26, Columbia University27, Eastern Virginia Medical School28, University of New South Wales29, Katholieke Universiteit Leuven30, Guy's Hospital31, Stanford University32, University of British Columbia33, Mayo Clinic34, Johns Hopkins University35, Korea University36, Uniformed Services University of the Health Sciences37, Jikei University School of Medicine38, University of Washington39, University of Siena40, University of East Anglia41, University of Adelaide42, Pusan National University43, University of Calgary44, University of Cincinnati45, University of North Carolina at Chapel Hill46, Cleveland Clinic47, University of Winnipeg48, Chulalongkorn University49, Cornell University50, National University of Singapore51, University of Alabama at Birmingham52, University of Alberta53, Capital Medical University54
TL;DR: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in the understanding and treatment of rhinologic disease.
Abstract: I. Executive summary BACKGROUND: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR-RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR-RS-2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence-based findings of the document. Methods ICAR-RS presents over 180 topics in the forms of evidence-based reviews with recommendations (EBRRs), evidence-based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results ICAR-RS-2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence-based management algorithm is provided. Conclusion This ICAR-RS-2021 executive summary provides a compilation of the evidence-based recommendations for medical and surgical treatment of the most common forms of RS.
299 citations
TL;DR: Recommendations for the most effective management of a patient with N‐ERD stressing the potential high morbidity and severity of the underlying asthma and rhinosinusitis are discussed and proposed.
Abstract: NSAID-exacerbated respiratory disease (N-ERD) is a chronic eosinophilic, inflammatory disorder of the respiratory tract occurring in patients with asthma and/or chronic rhinosinusitis with nasal polyps (CRSwNP), symptoms of which are exacerbated by NSAIDs, including aspirin. Despite some progress in understanding of the pathophysiology of the syndrome, which affects 1/10 of patients with asthma and rhinosinusitis, it remains a diagnostic and therapeutic challenge. In order to provide evidence-based recommendations for the diagnosis and management of N-ERD, a panel of international experts was called by the EAACI Asthma Section. The document summarizes current knowledge on the pathophysiology and clinical presentation of N-ERD pointing at significant heterogeneity of this syndrome. Critically evaluating the usefulness of diagnostic tools available, the paper offers practical algorithm for the diagnosis of N-ERD. Recommendations for the most effective management of a patient with N-ERD stressing the potential high morbidity and severity of the underlying asthma and rhinosinusitis are discussed and proposed. Newly described sub-phenotypes and emerging sub-endotypes of N-ERD are potentially relevant for new and more specific (eg, biological) treatment modalities. Finally, the document defines major gaps in our knowledge on N-ERD and unmet needs, which should be addressed in the future.
216 citations
University of Amsterdam1, University College London2, Ghent University3, Karolinska University Hospital4, University of Barcelona5, Lund University6, Humanitas University7, Université de Montréal8, First Faculty of Medicine, Charles University in Prague9, Eastern Virginia Medical School10, Guy's and St Thomas' NHS Foundation Trust11, Ghent University Hospital12, University of California, Los Angeles13, University of Pittsburgh14, Katholieke Universiteit Leuven15, University of North Carolina at Chapel Hill16
TL;DR: Novel therapies such as type 2 targeting biologics are emerging treatment options for patients with chronic inflammatory respiratory diseases, fulfilling the needs of severely uncontrolled patients and may soon also become available for CRSwNP patients.
Abstract: Novel therapies such as type 2 targeting biologics are emerging treatment options for patients with chronic inflammatory respiratory diseases, fulfilling the needs of severely uncontrolled patients. The majority of patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and over half of patients with asthma show a type 2 inflammatory signature in sinonasal mucosa and/or lungs. Importantly, both chronic respiratory diseases are frequent comorbidities, ensuring alleviation of both upper and lower airway pathology by systemic biological therapy. Type 2-targeting biologics such as anti-IgE, anti-IL4Rα, anti-IL5, and anti-IL5Rα have entered the market for selected pheno/endotypes of asthma patients and may soon also become available for CRSwNP patients. Given the high prevalence of chronic respiratory diseases and the high cost associated with biologics, patient selection is crucial in order to implement such therapies into chronic respiratory disease care pathways. The European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) organized a multidisciplinary Expert Board Meeting to discuss the positioning of biologics into the care pathways for CRSwNP patients with and without comorbid asthma.
198 citations
References
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University of Amsterdam1, Ghent University2, University of Chicago3, University of Pennsylvania4, Lund University5, Auckland City Hospital6, University of Antwerp7, University of New South Wales8, Katholieke Universiteit Leuven9, Guy's and St Thomas' NHS Foundation Trust10, Queen's University11, University of Zagreb12, Northwestern University13, Medical University of Łódź14, University of Aberdeen15, Medical University of South Carolina16, University of North Carolina at Chapel Hill17, University of Southampton18, University of São Paulo19, National University of Singapore20, Flinders University21
TL;DR: The European Position Paper on Rhinosinusitis and Nasal Polyps 2020 is the update of similar evidence based position papers published in 2005 and 2007 and 2012 and addresses areas not extensively covered in EPOS2012 such as paediatric CRS and sinus surgery.
Abstract: The European Position Paper on Rhinosinusitis and Nasal Polyps 2020 is the update of similar evidence based position papers published in 2005 and 2007 and 2012. The core objective of the EPOS2020 guideline is to provide revised, up-to-date and clear evidence-based recommendations and integrated care pathways in ARS and CRS. EPOS2020 provides an update on the literature published and studies undertaken in the eight years since the EPOS2012 position paper was published and addresses areas not extensively covered in EPOS2012 such as paediatric CRS and sinus surgery. EPOS2020 also involves new stakeholders, including pharmacists and patients, and addresses new target users who have become more involved in the management and treatment of rhinosinusitis since the publication of the last EPOS document, including pharmacists, nurses, specialised care givers and indeed patients themselves, who employ increasing self-management of their condition using over the counter treatments. The document provides suggestions for future research in this area and offers updated guidance for definitions and outcome measurements in research in different settings. EPOS2020 contains chapters on definitions and classification where we have defined a large number of terms and indicated preferred terms. A new classification of CRS into primary and secondary CRS and further division into localized and diffuse disease, based on anatomic distribution is proposed. There are extensive chapters on epidemiology and predisposing factors, inflammatory mechanisms, (differential) diagnosis of facial pain, allergic rhinitis, genetics, cystic fibrosis, aspirin exacerbated respiratory disease, immunodeficiencies, allergic fungal rhinosinusitis and the relationship between upper and lower airways. The chapters on paediatric acute and chronic rhinosinusitis are totally rewritten. All available evidence for the management of acute rhinosinusitis and chronic rhinosinusitis with or without nasal polyps in adults and children is systematically reviewed and integrated care pathways based on the evidence are proposed. Despite considerable increases in the amount of quality publications in recent years, a large number of practical clinical questions remain. It was agreed that the best way to address these was to conduct a Delphi exercise . The results have been integrated into the respective sections. Last but not least, advice for patients and pharmacists and a new list of research needs are included. The full document can be downloaded for free on the website of this journal: http://www.rhinologyjournal.com.
2,853 citations
TL;DR: Mepolizumab is an effective and well tolerated treatment that reduces the risk of asthma exacerbations in patients with severe eosinophilic asthma.
1,765 citations
TL;DR: Mepolizumab administered either intravenously or subcutaneously significantly reduced asthma exacerbations and was associated with improvements in markers of asthma control and the safety profile of mepolIZumab was similar to that of placebo.
Abstract: BACKGROUND: Some patients with severe asthma have frequent exacerbations associated with persistent eosinophilic inflammation despite continuous treatment with high-dose inhaled glucocorticoids with or without oral glucocorticoids. METHODS: In this randomized, double-blind, double-dummy study, we assigned 576 patients with recurrent asthma exacerbations and evidence of eosinophilic inflammation despite high doses of inhaled glucocorticoids to one of three study groups. Patients were assigned to receive mepolizumab, a humanized monoclonal antibody against interleukin-5, which was administered as either a 75-mg intravenous dose or a 100-mg subcutaneous dose, or placebo every 4 weeks for 32 weeks. The primary outcome was the rate of exacerbations. Other outcomes included the forced expiratory volume in 1 second (FEV1) and scores on the St. George's Respiratory Questionnaire (SGRQ) and the 5-item Asthma Control Questionnaire (ACQ-5). Safety was also assessed. RESULTS: The rate of exacerbations was reduced by 47% (95% confidence interval [CI], 29 to 61) among patients receiving intravenous mepolizumab and by 53% (95% CI, 37 to 65) among those receiving subcutaneous mepolizumab, as compared with those receiving placebo (P<0.001 for both comparisons). Exacerbations necessitating an emergency department visit or hospitalization were reduced by 32% in the group receiving intravenous mepolizumab and by 61% in the group receiving subcutaneous mepolizumab. At week 32, the mean increase from baseline in FEV1 was 100 ml greater in patients receiving intravenous mepolizumab than in those receiving placebo (P=0.02) and 98 ml greater in patients receiving subcutaneous mepolizumab than in those receiving placebo (P=0.03). The improvement from baseline in the SGRQ score was 6.4 points and 7.0 points greater in the intravenous and subcutaneous mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 4 points), and the improvement in the ACQ-5 score was 0.42 points and 0.44 points greater in the two mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 0.5 points) (P<0.001 for all comparisons). The safety profile of mepolizumab was similar to that of placebo. CONCLUSIONS: Mepolizumab administered either intravenously or subcutaneously significantly reduced asthma exacerbations and was associated with improvements in markers of asthma control. (Funded by GlaxoSmithKline; MENSA ClinicalTrials.gov number, NCT01691521.).
1,680 citations
TL;DR: In this paper, a randomized, double-blind trial involving 135 patients with severe eosinophilic asthma, compared the glucocorticoid-sparing effect of mepolizumab (at a dose of 100 mg) with that of placebo administered subcutaneously every 4 weeks for 20 weeks.
Abstract: Background Many patients with severe asthma require regular treatment with oral glucocorticoids despite the use of high-dose inhaled therapy. However, the regular use of systemic glucocorticoids can result in serious and often irreversible adverse effects. Mepolizumab, a humanized monoclonal antibody that binds to and inactivates interleukin-5, has been shown to reduce asthma exacerbations in patients with severe eosinophilic asthma. Methods In a randomized, double-blind trial involving 135 patients with severe eosinophilic asthma, we compared the glucocorticoid-sparing effect of mepolizumab (at a dose of 100 mg) with that of placebo administered subcutaneously every 4 weeks for 20 weeks. The primary outcome was the degree of reduction in the glucocorticoid dose (90 to 100% reduction, 75 to less than 90% reduction, 50 to less than 75% reduction, more than 0 to less than 50% reduction, or no decrease in oral glucocorticoid dose, a lack of asthma control during weeks 20 to 24, or withdrawal from treatment)....
1,249 citations
Book•
03 Feb 2013
TL;DR: In this paper, the authors present a survey of Bayesian methods for health-care evaluation, focusing on the following: 1.1 What is probability? 2.2 Random variables, parameters and likelihood.
Abstract: Preface. List of examples. 1. Introduction. 1.1 What are Bayesian methods? 1.2 What do we mean by 'health--care evaluation'? 1.3 A Bayesian approach to evaluation. 1.4 The aim of this book and the intended audience. 1.5 Structure of the book. 2. Basic Concepts from Traditional Statistical Analysis. 2.1 Probability. 2.1.1 What is probability? 2.1.2 Odds and log--odds. 2.1.3 Bayes theorem for simple events. 2.2 Random variables, parameters and likelihood. 2.2.1 Random variables and their distributions. 2.2.2 Expectation, variance, covariance and correlation. 2.2.3 Parametric distributions and conditional independence. 2.2.4 Likelihoods. 2.3 The normal distribution. 2.4 Normal likelihoods. 2.4.1 Normal approximations for binary data. 2.4.2 Normal likelihoods for survival data. 2.4.3 Normal likelihoods for count responses. 2.4.4 Normal likelihoods for continuous responses. 2.5 Classical inference. 2.6 A catalogue of useful distributionsaeo. 2.6.1 Binomial and Bernoulli. 2.6.2 Poisson. 2.6.3 Beta. 2.6.4 Uniform. 2.6.5 Gamma. 2.6.6 Root--inverse--gamma. 2.6.7 Half--normal. 2.6.8 Log--normal. 2.6.9 Student's t. 2.6.10 Bivariate normal. 2.7 Key points. Exercises. 3. An Overview of the Bayesian Approach. 3.1 Subjectivity and context. 3.2 Bayes theorem for two hypotheses. 3.3 Comparing simple hypotheses: likelihood ratios and Bayes factors. 3.4 Exchangeability and parametric modellingaeo. 3.5 Bayes theorem for general quantities. 3.6 Bayesian analysis with binary data. 3.6.1 Binary data with a discrete prior distribution. 3.6.2 Conjugate analysis for binary data. 3.7 Bayesian analysis with normal distributions. 3.8 Point estimation, interval estimation and interval hypotheses. 3.9 The prior distribution. 3.10 How to use Bayes theorem to interpret trial results. 3.11 The 'credibility' of significant trial resultsaeo. 3.12 Sequential use of Bayes theoremaeo. 3.13 Predictions. 3.13.1 Predictions in the Bayesian framework. 3.13.2 Predictions for binary dataaeo. 3.13.3 Predictions for normal data. 3.14 Decision--making. 3.15 Design. 3.16 Use of historical data. 3.17 Multiplicity, exchangeability and hierarchical models. 3.18 Dealing with nuisance parametersaeo. 3.18.1 Alternative methods for eliminating nuisance parametersaeo. 3.18.2 Profile likelihood in a hierarchical modelaeo. 3.19 Computational issues. 3.19.1 Monte Carlo methods. 3.19.2 Markov chain Monte Carlo methods. 3.19.3 WinBUGS. 3.20 Schools of Bayesians. 3.21 A Bayesian checklist. 3.22 Further reading. 3.23 Key points. Exercises. 4. Comparison of Alternative Approaches to Inference. 4.1 A structure for alternative approaches. 4.2 Conventional statistical methods used in health--care evaluation. 4.3 The likelihood principle, sequential analysis and types of error. 4.3.1 The likelihood principle. 4.3.2 Sequential analysis. 4.3.3 Type I and Type II error. 4.4 P--values and Bayes factorsaeo. 4.4.1 Criticism of P--values. 4.4.2 Bayes factors as an alternative to P--values: simple hypotheses. 4.4.3 Bayes factors as an alternative to P--values: composite hypotheses. 4.4.4 Bayes factors in preference studies. 4.4.5 Lindley's paradox. 4.5 Key points. Exercises. 5. Prior Distributions. 5.1 Introduction. 5.2 Elicitation of opinion: a brief review. 5.2.1 Background to elicitation. 5.2.2 Elicitation techniques. 5.2.3 Elicitation from multiple experts. 5.3 Critique of prior elicitation. 5.4 Summary of external evidenceaeo. 5.5 Default priors. 5.5.1 'Non--informative' or 'reference' priors: 5.5.2 'Sceptical' priors. 5.5.3 'Enthusiastic' priors. 5.5.4 Priors with a point mass at the null hypothesis ('lump--and--smear' priors)aeo. 5.6 Sensitivity analysis and 'robust' priors. 5.7 Hierarchical priors. 5.7.1 The judgement of exchangeability. 5.7.2 The form for the random--effects distribution. 5.7.3 The prior for the standard deviation of the random effectsaeo. 5.8 Empirical criticism of priors. 5.9 Key points. Exercises. 6. Randomised Controlled Trials. 6.1 Introduction. 6.2 Use of a loss function: is a clinical trial for inference or decision? 6.3 Specification of null hypotheses. 6.4 Ethics and randomisation: a brief review. 6.4.1 Is randomisation necessary? 6.4.2 When is it ethical to randomise? 6.5 Sample size of non--sequential trials. 6.5.1 Alternative approaches to sample--size assessment. 6.5.2 'Classical power': hybrid classical--Bayesian methods assuming normality. 6.5.3 'Bayesian power'. 6.5.4 Adjusting formulae for different hypotheses. 6.5.5 Predictive distribution of power and necessary sample size. 6.6 Monitoring of sequential trials. 6.6.1 Introduction. 6.6.2 Monitoring using the posterior distribution. 6.6.3 Monitoring using predictions: 'interim power'. 6.6.4 Monitoring using a formal loss function. 6.6.5 Frequentist properties of sequential Bayesian methods. 6.6.6 Bayesian methods and data monitoring committees. 6.7 The role of 'scepticism' in confirmatory studies. 6.8 Multiplicity in randomised trials. 6.8.1 Subset analysis. 6.8.2 Multi--centre analysis. 6.8.3 Cluster randomization. 6.8.4 Multiple endpoints and treatments. 6.9 Using historical controlsaeo. 6.10 Data--dependent allocation. 6.11 Trial designs other than two parallel groups. 6.12 Other aspects of drug development. 6.13 Further reading. 6.14 Key points. Exercises. 7. Observational Studies. 7.1 Introduction. 7.2 Alternative study designs. 7.3 Explicit modelling of biases. 7.4 Institutional comparisons. 7.5 Key points. Exercises. 8. Evidence Synthesis. 8.1 Introduction. 8.2 'Standard' meta--analysis. 8.2.1 A Bayesian perspective. 8.2.2 Some delicate issues in Bayesian meta--analysis. 8.2.3 The relationship between treatment effect and underlying risk. 8.3 Indirect comparison studies. 8.4 Generalised evidence synthesis. 8.5 Further reading. 8.6 Key points. Exercises. 9. Cost--effectiveness, Policy--Making and Regulation. 9.1 Introduction. 9.2 Contexts. 9.3 'Standard' cost--effectiveness analysis without uncertainty. 9.4 'Two--stage' and integrated approaches to uncertainty in cost--effectiveness modeling. 9.5 Probabilistic analysis of sensitivity to uncertainty about parameters: two--stage approach. 9.6 Cost--effectiveness analyses of a single study: integrated approach. 9.7 Levels of uncertainty in cost--effectiveness models. 9.8 Complex cost--effectiveness models. 9.8.1 Discrete--time, discrete--state Markov models. 9.8.2 Micro--simulation in cost--effectiveness models. 9.8.3 Micro--simulation and probabilistic sensitivity analysis. 9.8.4 Comprehensive decision modeling. 9.9 Simultaneous evidence synthesis and complex cost--effectiveness modeling. 9.9.1 Generalised meta--analysis of evidence. 9.9.2 Comparison of integrated Bayesian and two--stage approach. 9.10 Cost--effectiveness of carrying out research: payback models. 9.10.1 Research planning in the public sector. 9.10.2 Research planning in the pharmaceutical industry. 9.10.3 Value of information. 9.11 Decision theory in cost--effectiveness analysis, regulation and policy. 9.12 Regulation and health policy. 9.12.1 The regulatory context. 9.12.2 Regulation of pharmaceuticals. 9.12.3 Regulation of medical devices. 9.13 Conclusions. 9.14 Key points. Exercises. 10. Conclusions and Implications for Future Research. 10.1 Introduction. 10.2 General advantages and problems of a Bayesian approach. 10.3 Future research and development. Appendix: Websites and Software. A.1 The site for this book. A.2 Bayesian methods in health--care evaluation. A.3 Bayesian software. A.4 General Bayesian sites. References. Index.
1,038 citations