Approaches to modelling the cost-effectiveness of interventions for heart failure: a systematic review

Poster presentationOBJECTIVES: To review modelling methods used to assess the cost-effectiveness of interventions for heart failure (HF). METHODS: A systematic search of the literature up to September 2016 across Medline, Embase, Cochrane Library, EconLit and CINAHL databases. We included studies that reported a model-based evaluation, including both costs and health impacts, of a HF intervention. Studies reporting only cost-effectiveness analyses alongside a clinical trial were excluded. RESULTS: We identified 54 publications describing 52 economic models associated with HF interventions. The model-based evaluations comprised surgical (n=20), medical (n=16), service-level (e.g. telehealth, specialist clinics) (n=9) or screening-/monitoring-type interventions (n=4), or assessed disease management (n=2). One study compared multiple interventions. The most common modelling framework was a Markov cohort method (n=41); with models predominantly modelling disease progression via New York Heart Association grade or using a simple two-state (alive/dead) model. Several studies additionally included transition states for hospitalisation events. Two studies adapted the Markov cohort approach for sub-group analyses using risk equations. Eight studies reported a patient-level discrete event simulation approach, and four studies were decision trees. Key structural inputs to model development were data used to model mortality and to predict hospital admissions. CONCLUSIONS: A range of modelling approaches have been used successfully to assess the cost-effectiveness of HF interventions. Whilst the simple Markov cohort approach appears appropriate for the decision problem stated in most cases (i.e. estimating cost effectiveness), other methods have been used to good effect. To date modelling has not addressed the specific nature of the impact of HF on quality of life/ wellbeing, other than via use of NYHA and/or impact of hospital admissions. Future modelling may further consider this through use of natural history states using health states informed by health outcome measures commonly used in HF.This work was carried out as part of the REACH-HF trial, an independent research programme funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research scheme (Reference Number RP-PG-1210-12004

Geometry of the Prytz Planimeter

The Prytz planimeter is a simple example of a system governed by a non-holonomic constraint. It is unique among planimeters in that it measures something more subtle than area, combining the area, centroid and other moments of the region being measured, with weights depending on the length of the planimeter. As a tool for measuring area, it is most accurate for regions that are small relative to its length. The configuration space of the planimeter is a non-principal circle bundle acted on by SU(1,1), (isom. to SL(2,R)). The motion of the planimeter is realized as parallel translation for a connection on this bundle and for a connection on a principal SU(1,1)-bundle. The holonomy group is SU(1,1). As a consequence, the planimeter is an example of a system with a phase shift on the circle that is not a simple rotation. There is a qualitative difference in the holonomy when tracing large regions as opposed to small ones. Generic elements of SU(1,1) act on S^1 with two fixed points or with no fixed points. When tracing small regions, the holonomy acts without fixed points. Menzin's conjecture states (roughly) that if a planimeter of length L traces the boundary of a region with area A > pi L^2, then it exhibits an asymptotic behavior and the holonomy acts with two fixed points, one attracting and one repelling. This is obvious if the region is a disk, and intuitively plausible if the region is convex and A >> pi L^2. A proof of this conjecture is given for a special case, and the conjecture is shown to imply the isoperimetric inequality.Comment: AmS-TeX, 23 pages, 12 figures in 2 *.gif files. To appear in Reports on Mathematical Physics. Part of proceedings of Workshop on Non-holonomic Constraints in Dynamics, Univ. of Calgary, Aug. 199

Correspondence between geometrical and differential definitions of the sine and cosine functions and connection with kinematics

In classical physics, the familiar sine and cosine functions appear in two forms: (1) geometrical, in the treatment of vectors such as forces and velocities, and (2) differential, as solutions of oscillation and wave equations. These two forms correspond to two different definitions of trigonometric functions, one geometrical using right triangles and unit circles, and the other employing differential equations. Although the two definitions must be equivalent, this equivalence is not demonstrated in textbooks. In this manuscript, the equivalence between the geometrical and the differential definition is presented assuming no a priori knowledge of the properties of sine and cosine functions. We start with the usual length projections on the unit circle and use elementary geometry and elementary calculus to arrive to harmonic differential equations. This more general and abstract treatment not only reveals the equivalence of the two definitions but also provides an instructive perspective on circular and harmonic motion as studied in kinematics. This exercise can help develop an appreciation of abstract thinking in physics.Comment: 6 pages including 1 figur

Immunosuppressive therapy for kidney transplantation in children and adolescents: systematic review and economic evaluation.

This is the final version of the article. Available from the publisher via the DOI in this record.BACKGROUND: End-stage renal disease is a long-term irreversible decline in kidney function requiring kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation followed by induction and maintenance immunosuppressive therapy to reduce the risk of kidney rejection and prolong graft survival. OBJECTIVES: To systematically review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect,(®) Novartis Pharmaceuticals) and rabbit antihuman thymocyte immunoglobulin (Thymoglobuline,(®) Sanofi) as induction therapy and immediate-release tacrolimus [Adoport(®) (Sandoz); Capexion(®) (Mylan); Modigraf(®) (Astellas Pharma); Perixis(®) (Accord Healthcare); Prograf(®) (Astellas Pharma); Tacni(®) (Teva); Vivadex(®) (Dexcel Pharma)], prolonged-release tacrolimus (Advagraf,(®) Astellas Pharma); belatacept (BEL) (Nulojix,(®) Bristol-Myers Squibb), mycophenolate mofetil (MMF) [Arzip(®) (Zentiva), CellCept(®) (Roche Products), Myfenax(®) (Teva), generic MMF is manufactured by Accord Healthcare, Actavis, Arrow Pharmaceuticals, Dr Reddy's Laboratories, Mylan, Sandoz and Wockhardt], mycophenolate sodium, sirolimus (Rapamune,(®) Pfizer) and everolimus (Certican,(®) Novartis Pharmaceuticals) as maintenance therapy in children and adolescents undergoing renal transplantation. DATA SOURCES: Clinical effectiveness searches were conducted to 7 January 2015 in MEDLINE (via Ovid), EMBASE (via Ovid), Cochrane Central Register of Controlled Trials (via Wiley Online Library) and Web of Science [via Institute for Scientific Information (ISI)], Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Health Technology Assessment (HTA) (The Cochrane Library via Wiley Online Library) and Health Management Information Consortium (via Ovid). Cost-effectiveness searches were conducted to 15 January 2015 using a costs or economic literature search filter in MEDLINE (via Ovid), EMBASE (via Ovid), NHS Economic Evaluation Databases (via Wiley Online Library), Web of Science (via ISI), Health Economic Evaluations Database (via Wiley Online Library) and EconLit (via EBSCOhost). REVIEW METHODS: Titles and abstracts were screened according to predefined inclusion criteria, as were full texts of identified studies. Included studies were extracted and quality appraised. Data were meta-analysed when appropriate. A new discrete time state transition economic model (semi-Markov) was developed; graft function, and incidences of acute rejection and new-onset diabetes mellitus were used to extrapolate graft survival. Recipients were assumed to be in one of three health states: functioning graft, graft loss or death. RESULTS: Three randomised controlled trials (RCTs) and four non-RCTs were included. The RCTs only evaluated BAS and tacrolimus (TAC). No statistically significant differences in key outcomes were found between BAS and placebo/no induction. Statistically significantly higher graft function (p < 0.01) and less biopsy-proven acute rejection (odds ratio 0.29, 95% confidence interval 0.15 to 0.57) was found between TAC and ciclosporin (CSA). Only one cost-effectiveness study was identified, which informed NICE guidance TA99. BAS [with TAC and azathioprine (AZA)] was predicted to be cost-effective at £20,000-30,000 per quality-adjusted life year (QALY) versus no induction (BAS was dominant). BAS (with CSA and MMF) was not predicted to be cost-effective at £20,000-30,000 per QALY versus no induction (BAS was dominated). TAC (with AZA) was predicted to be cost-effective at £20,000-30,000 per QALY versus CSA (TAC was dominant). A model based on adult evidence suggests that at a cost-effectiveness threshold of £20,000-30,000 per QALY, BAS and TAC are cost-effective in all considered combinations; MMF was also cost-effective with CSA but not TAC. LIMITATIONS: The RCT evidence is very limited; analyses comparing all interventions need to rely on adult evidence. CONCLUSIONS: TAC is likely to be cost-effective (vs. CSA, in combination with AZA) at £20,000-30,000 per QALY. Analysis based on one RCT found BAS to be dominant, but analysis based on another RCT found BAS to be dominated. BAS plus TAC and AZA was predicted to be cost-effective at £20,000-30,000 per QALY when all regimens were compared using extrapolated adult evidence. High-quality primary effectiveness research is needed. The UK Renal Registry could form the basis for a prospective primary study. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014013544. FUNDING: The National Institute for Health Research HTA programme.The research reported in this issue of the journal was commissioned and funded by the HTA programme on behalf of NICE as project number 09/119/01. The protocol was agreed in July 2014. The assessment report began editorial review in May 2015 and was accepted for publication in October 2015. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report. This report presents independent research funded by the National Institute for Health Research (NIHR). The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health

Early access schemes for innovative health technologies: the views of international stakeholders

This is the final version. Available on open access from Cambridge University Press via the DOI in this recordOBJECTIVES: Early access schemes (EASs) are approaches used by payers to balance and facilitate earlier patient access to innovative health technologies while evidence generation is ongoing. Schemes require investment from payers and are associated with significant risk since not all technologies will be routinely reimbursed. The purpose of this study was to gain the perspectives of policy experts about the key challenges for EASs and potential solutions for their optimal design and implementation. METHODS: Two virtual workshops were convened including (i) UK-based policy experts (England, Wales, and Scotland) and (ii) representatives from multiple healthcare systems (England, France, Sweden, Canada, Poland, and Norway). Participants were encouraged to share their experiences with EASs in their healthcare system and highlight key challenges for policy makers. Discussions were transcribed and analyzed using framework analysis. RESULTS: Participants agreed that EASs have value when targeted toward innovative technologies with the potential for significant clinical benefit in an area of high unmet need. Participants discussed potential solutions to the challenges faced by payers implementing EASs, including defining eligibility criteria, supporting evidence generation, and approaches to reimbursement. CONCLUSIONS: Participants agreed that EASs are one possible solution for their healthcare systems and have the potential to deliver significant clinical value to patients. However, widespread adoption of EASs is limited due to concerns about the risks for patients and healthcare budgets, further solutions are needed to deliver EASs for targeted therapies.NHS Englan

An evaluation of managed access agreements in England based on stakeholder experience

This is the final version. Available on open access from Cambridge University Press via the DOI in this recordOBJECTIVES: The objective of this research was to evaluate managed access policy in England, drawing upon the expertise of a range of stakeholders involved in its implementation. METHODS: Seven focus groups were conducted with payer and health technology assessment representatives, clinicians, and representatives from industry and patient/carer organizations within England. Transcripts were analyzed using framework analysis to identify stakeholders' views on the successes and challenges of managed access policy. RESULTS: Stakeholders discussed the many aims of managed access within the National Health Service in England, and how competing aims had affected decision making. While stakeholders highlighted a number of priorities within eligibility criteria for managed access agreements (MAAs), stakeholders agreed that strict eligibility criteria would be challenging to implement due to the highly variable nature of innovative technologies and their indications. Participants highlighted challenges faced with implementing MAAs, including evidence generation, supporting patients during and after the end of MAAs, and agreeing and reinforcing contractual agreements with industry. CONCLUSIONS: Managed access is one strategy that can be used by payers to resolve uncertainty for innovative technologies that present challenges for reimbursement and can also deliver earlier access to promising technologies for patients. However, participants cautioned that managed access is not a "silver bullet," and there is a need for greater clarity about the aims of managed access and how these should be prioritized in decision making. Discussions between key stakeholders involved in managed access identified challenges with implementing MAAs and these experiences should be used to inform future managed access policy.NHS Englan

An analysis of uncertainties and data collection agreements in the cancer drugs fund

Background: Managed Access Agreements (MAAs) are a commercial arrangement that provide patients earlier access to innovative health technologies while uncertainties in the evidence base are resolved through data collection. In the UK, data collection agreements (DCAs) outline the evidence that will be collected during the MAA period and are intended to resolve uncertainties in the clinical- and cost-effectiveness of a technology sufficient for the National Institute of Health and Care Excellence (NICE) committee to make a final decision on reimbursement. Objective: The aim of this study was to identify the primary uncertainties leading to a recommendation for entry to the Cancer Drugs Fund (CDF) and evaluate how the corresponding DCAs attempt to address these. Methods: A database of MAAs agreed within the CDF was compiled with coverage between July 2016 and December 2020 (the time during which evidence generation was routinely collected within the CDF up until the time of analysis). Uncertainties in the evidence base for technologies entering the CDF were analysed alongside the outcomes planned for data collection during the MAA. These data provide an overview of the key uncertainties surrounding health technologies in the CDF on entry and the types of evidence targeted by DCAs. Results: In the assessment of 39 Cancer Drugs Fund (CDF) cases, NICE committees identified a total of 108 key uncertainties in cost-effectiveness estimates. Overall survival was the most commonly identified uncertainty, followed by generalisability of the evidence to the target population. DCAs specified a range of outcomes relevant to understanding the clinical effectiveness of the technology, though fewer than half (43.6%) of the DCAs addressed all the key uncertainties identified by the NICE committee. Conclusion: The analysis indicated that data collection within the CDF is not sufficient to resolve all the uncertainties identified by the NICE committee, meaning that other approaches will be needed at re-appraisal to ensure that the NICE committee can reach a final decision on reimbursement

Ozanimod for treating moderately to severely active ulcerative colitis [ID3841] A Single Technology Appraisal

This report was commissioned by the NIHR Systematic Reviews Programme as project number 13/54/43Executive Summary: This summary provides a brief overview of the key issues identified by the evidence review group (ERG) as being potentially important for decision-making. It also includes the ERG’s preferred assumptions and the resulting incremental cost-effectiveness ratios (ICERs). • Section 1.1 provides an overview of the key issues and the differences in the assumptions of the company and the ERG in economic analysis. • Section 1.2 provides an overview of key model outcomes and the modelling assumptions that have the greatest effect on the ICER. • Sections 1.3 to 1.5 explain the key issues in more detail. Background information on the condition, technology and evidence and information on non-key issues are in the main ERG report. • Sections 1.6 and 1.7 provide an overview of the ERG’s preferred base case and sensitivity analyses undertaken by the ERG. All issues identified represent the ERG’s view, not the opinion of the National Institute for Health and Care Excellence (NICE)