Nice Method Research Articles

HTA105 Has the NICE Methods and Processes Update Accelerated Access to Rare Disease Technologies Routed Via the Single Technology Appraisal (STA) Pathway?

HTA105 Has the NICE Methods and Processes Update Accelerated Access to Rare Disease Technologies Routed Via the Single Technology Appraisal (STA) Pathway?

Flexibility in assessment of rare disease technologies via NICE's single technology appraisal route: a thematic analysis.

Aim: NICE's highly specialized technology (HST) evaluations are highly restrictive in terms of entry criteria and as a consequence, the vast majority of rare disease medicines are assessed through NICE's standard, single technology appraisal (STA) route. We explored whether NICE shows flexibility and pragmatism when evaluating treatments for rare diseases through its STA process. Materials & methods: We matched a sample of recent, randomly selected STAs for rare diseases to STAs for non-rare diseases and conducted a thematic analysis to identify patterns in NICE's decision-making, with a specific focus on the application of NICE's published methods and the handling of uncertainty. Results: Three themes emerged where some flexibility was shown: 'handling of uncertainty and discretion', 'application of NICE methods' and 'commercial arrangements'. Rare disease technologies were generally subject to longer appraisal times than those for non-rare diseases. Conclusion: Although NICE shows a degree of flexibility and pragmatism toward uncertainties in the evidence base for rare disease medicines, this is often off-set by a lengthy appraisal process, which can lead to delays in patients receiving vital treatment.

Effects of dual synthetic jets on longitudinal aerodynamic characteristics of a flying wing layout

A novel method of flight control based on dual synthetic jets (DSJ) is proposed and applied to a large-sweep flying wing aircraft with a hybrid flow mode of leading-edge vortex (LEV) and spanwise separation. An array of dual synthetic jet actuators (DSJAs) is placed along the leading edge to explore its aerodynamic control characteristics and control mechanism. The comparison with synthetic jets (SJ) is implemented to show the differences. Results show that DSJ could delay stalling angle of 6° and promote Cl with greater increments at large attack of angles (AOAs). At AOA of 36°, there was an obvious increase of 23.12% in Cl. Cd decreases at small AOAs, while augments sharply when AOA is larger than 26°. Nose-up moment could be improved. Above features indicate that leading-edge DSJ is not only a nice method of lift enhancement but also an efficient way of flight control. In the fuselage section, DSJ has functions of strengthening LEV, delaying the LEV breakdown and even regenerating LEV at large AOAs, which enhances the bleeding and improves the ability of resisting the reverse pressure gradient, thus totally suppressing the separation and forming the larger leading-edge suction. In the wing section, DSJ acts as a “LEV generator”. Reconstructed LEV could interact with the initial spanwise separation, emerging a hybrid flow mode of “streamers” and “rollers”, in which flow energy could be augmented and separation is partly suppressed. The comparison with SJ supports that the larger leading-edge suction and stronger LEV could be achieved by DSJ, which generate greater increments of Cl and Cm. Maximum Cl increments achieved by DSJ and SJ are respectively 23.12% and 16.91% of Cl without control, meaning DSJ has the higher applying potential in flight control with the same energy consumption.

Comparison of methods to characterize the penetration of hot melt adhesive into paper

Abstract In the use of hot melt adhesives in the production of paper-based packaging, the controlled penetration of the adhesive is important to obtain rapid setting rates, good bond strength, and the efficient use of adhesive. Measuring adhesive penetration depth has been limited to cross-sectional images, but quantifying the depth of penetration is difficult from these images. No quantitative method is well established in the literature. Four different techniques are compared to quantitatively measure adhesive penetration depth. Two methods involve separating the paperboard from the adhesive layer. Two other methods use of silicone oil penetration and mercury porosimetry to measure the decrease of pore volume after the adhesive is applied. These methods are compared with samples generated for various parameters. Experiments were conducted using a typical hot melt glue on uncoated and coated paperboard sample. Cross-sectional images from Scanning Electron Microscopy (SEM) confirm the penetration of some samples. The accuracy and repeatability of these methods were compared. Because of some issues with trying to repeatably remove the paper layer for the weight and thickness methods, and the time and cost of the mercury porosimeter method, the silicone oil method is a nice method to characterize the adhesive penetration depth.

Outcome of Core out Fistulectomy with Anal Spincter Reconstruction and Primary Repair of Internal Opening in the Treatment of Complex Anal Fistula; A Experience of 30 Cases

Background: The principal of management of anal fistula include closure of interior opening of fistula tract, drainage of contamination or necrotic tissue, and eradication of fistulous tract with maintenance of sphincter function. The selection of surgical operation (simple fistulotomy, fistulectomy, seton placement, development flap, fibrin glue or anal plug) is decided with the aid of the route of the fistula tracts and continence status. Objectives: The aim of the study was to determine the surgical technique “core out fistulectomy with anal sphincter reconstruction and primary closure of internal opening” in the treatment of trans-sphincteric fistula (high type or long tract) or supra-sphincteric fistula in terms of fistula healing, morbidity, recurrence and anal continence. Methods: This prospective observational study was carried out in the Department of Surgery Dr Amanat khan hospital and other private hospitals, Dhaka, Bangladesh, during 5th March 2020 to 10th April 2022. A total 30 patients between the age group 20 to 70 years who were diagnosed with Fistula-in-Ano(Complex Variety) which underwent Core out Fistulectomy with Anal Spincter Reconstruction and Primary Repair of Internal Opening. This analysis was done using SPSS 24 software version. The level of significance was set to 5% (p < 0.05). Results: There were 30 (91%) men and three (9%) women with a median age of 42 years. The common anal fistula type was high transsphincteric fistula in 31 patients with deep postanal abscess in two patients and two patients were suprasphincteric fistula. Conclusions: Core out fistulectomy with anal sphincter reconstruction and major closure of inner opening is a secure and nice method for excessive trans-sphincteric fistula. It has desirable useful results and no disturbance of continence. This has to be viewed in the cure of high trans-sphincteric fistula.

New Galois hulls of generalized Reed-Solomon codes

Most recently, Gao et al. found a nice method to investigate the Euclidean hulls of generalized Reed-Solomon codes in terms of Goppa codes. In this note, we extend the results to general Galois hull. We prove that the Galois hulls of some GRS codes are still GRS codes. We also give some examples on Galois LCD and self-dual MDS codes. Compare with known results, the Galois hulls of GRS codes obtained in this work have flexible parameters.

From the Editor

I hope this issue finds you well and you are enjoying the summer.In this issue, Will Frazier explains the NICE Method and introduces the NICE-R model. Eric Sundheim, Ben Towne, and Jeff Faust provide their thoughts on the double backsolve method. Finally, Gil Mathews provides an excellent summary of the application of valuation discounts in oppression cases by state. Thanks to all of our authors for sharing their insights.I would like to this opportunity to thank the Business Valuation Review's Editorial Review Board, who are all listed on this inside cover of the Business Valuation Review. This publication would not be possible without their time and contributions not only reviewing articles and preparing submissions, but also with their insightful and thoughtful comments, which make this journal what it is.As always, we invite our readers to submit articles on new or interesting content. Letters to the editor, which can range from commentary on current or past articles, practice tips or general observations, are also welcome. Feel free to e-mail me (kgarcia@finresearch.com) any thoughts for articles or letters you may have, and I will be happy to discuss those with you.Please enjoy this issue and be well.Kyle

Methods used for indirect comparisons of systemic treatments for psoriasis. A systematic review.

Indirect comparisons (including network meta-analyses [NMAs]) allow us to compare benefits and risks of multiple interventions for the same clinical condition when head-to-head comparisons are not feasible. To provide guidance to the clinical community on better understanding indirect comparison methods to help them to interpret their results by applying two quality standards to published indirect comparisons of systemic biologics for moderate to severe psoriasis. A systematic literature review (SLR) of published indirect comparisons of biologics for the treatment of moderate to severe psoriasis in adults was conducted. Data extraction was performed using a predefined subset of NICE TSD7 (National Institute for Health and Care Excellence Technical Support Document 7) checklist questions and methods used to perform each analysis were descriptively compared. Methodological quality of the SLR underlying each indirect comparison was assessed using AMSTAR 2 (A MeaSurement Tool to Assess systematic Reviews version 2). Twenty-two NMAs and four adjusted indirect comparisons (AICs) were identified. Although there were some similarities, for example, application of Bayesian random-effects models, several important methodological aspects varied considerably across NMAs identified, for example, classes of drugs, number of treatments and studies included, reporting and handling of different doses, and reporting of both checks for and investigations of inconsistency. Methodological comparisons across AICs were limited by the small number. The quality of most underlying SLRs described, assessed as overall level of confidence in the results, was 'critically low'. Understanding that there are different methodologies employed to answer differing research questions is key to helping clinicians to interpret the indirect evidence currently available in psoriasis.

Acceptability of Manufacturer-Proposed Utility Values for NICE Cancer Medicine Appraisals: Analysis of Manufacturers' Information Sources.

The National Institute for Health and Care Excellence's (NICE) method guide for technology appraisals (TAs) encourages medicine manufacturers to use the EuroQol 5 Dimensions (EQ-5D) in relevant clinical trials to obtain utility values; however, the EQ-5D may have low sensitivity when compared to disease-specific measures. This study investigated whether the NICE TA committee's acceptance of manufacturer-proposed utility values is dependent on the manufacturers' sources of the utility values. Using publicly available data for 2011-2020, we identified 136 single TAs of cancer medicines, the health-related quality-of-life-measures used in relevant clinical trials, manufacturers' sources of utility values, and the NICE TA committee's acceptance of these values. Fisher's exact tests were performed to compare the acceptability of different value sources and reasons for non-acceptance. The number of appraisals for which the EQ-5D in the relevant clinical trials was the source of the manufacturer-proposed utility values increased continuously over time. The TA committee's acceptance of values was not dependent on the information source. In cases where a submission for which the information source was the EQ-5D was rejected, the reason was generally related to inappropriate values for the UK population or inappropriate data adjustment, not data reliability. Our results demonstrated that according with the NICE's method guide regarding utility values does not guarantee acceptance by the TA committee. Manufacturers must consider in advance possible differences between their clinical trials and clinical practice in the UK and refine plans for EQ-5D measurement in order to obtain convincing evidence.

POSB131 Equity and Health Inequalities: Should DCEA be Considered for Decision Making in the United Kingdom?

In the UK, NICE uses cost-effectiveness analysis (CEA) to determine whether a technology will be reimbursed and provided within the NHS. However, CEA does not capture the impact of a new health technology on inequalities between population groups. Distributional cost-effectiveness analysis (DCEA), which is currently being explored in the NICE methods review, is an additional “layer” that can be added to a CEA model to include formal analysis within the decision making process.

PMU72 Digital Health Technology PILOT Evaluation

NICE was commissioned by NHS England to conduct an evaluation pilot for digital health technologies (DHTs) during 2019/20. The pilot aimed to produce national NICE guidance on cost saving DHTs, consistent with the policy aims of the forthcoming NHS England funding mandate for MedTech. The pilot evaluation for DHTs was based on the existing NICE medical technologies guidance process and methods which aim to evaluate the clinical effectiveness and economic impact of the technology. The key stages in the evaluation are scoping, evidence submission, evidence review, committee decision-making and guidance publication. The pilot process included some variations suited for DHTs such as a technical assessment, inclusion of digital expert advisers, revision of the evidence submission process and the option of collecting additional data before the committee. The pilot involved the assessment of 5 DHTs chosen by NHS England. Three of the technologies did not obtain regulatory approval within the expected timeframe and had sparse clinical evidence and so the guidance development did not proceed beyond the evidence review stage. Guidance development is proceeding on 2 technologies and will be published later this year. Valuable lessons were learnt about developing NICE guidance on a range of DHTs. Examples include a proposal that regulatory approval should be a pre-requisite for medical technologies guidance development and that splitting the company submission into 2 parts enabled the early identification of topics with insufficient clinical evidence to proceed further to the committee and also reduced the burden on companies. The pilot evaluation project successfully explored the development of NICE’s medical technologies guidance for 5 DHTs. Lessons learnt will be used to update the current NICE medical technologies guidance development process and methods to facilitate routine guidance development for DHTs.

PCN241 Complex Innovative Design Trials: Too Complex for Market Access?

Complex innovative design (CID) trials aim to address multiple clinical questions, including efficacy in biomarker-selected patients, specific cancer cohorts or combination regimens. While CID trials could speed up the traditional route to European Medicines Agency marketing authorisation, they can be more challenging to evaluate through Health Technology Assessments (HTA) versus conventional randomized controlled trials. This research explores whether CID oncology trials can accelerate time to regulatory approval and patient access while maintaining optimised pricing and market access outcomes. Thirty-minute, qualitative, in-depth interviews were conducted with payer advisors from France, Germany and the UK to understand perspectives on HTA outcomes for larotrectinib and expectations for entrectinib, histology-independent cancer drugs studied in CID trials and targeting neurotrophic tyrosine receptor kinase (NTRK) solid tumours. In England, following the submission of a revised price, larotrectinib was recommended for inclusion in the Cancer Drugs Fund (CDF). This allows for data collection to address clinical uncertainties, stemming from the pooled analysis of single-arm trials with limited patient numbers, while providing access. In contrast, larotrectinib has broad access in Germany though its price may have been negatively impacted by its ‘no additional benefit’ rating based on clinical uncertainties. In France, early access to larotrectinib was provided via a cohort Temporary Use Authorisation (ATU), however payers expect less favourable HTA outcomes given uncertainties in the clinical benefit due to the trial design. Payers expect entrectinib will face similar hurdles to larotrectinib which, coupled with reduced unmet needs, will negatively impact pricing and market access opportunity. CID trials create significant uncertainty on the benefit of oncology drugs assessed using existing HTA frameworks, risking negative reimbursement outcomes. The availability of managed/early access agreements can be leveraged by manufacturers for timely access. Additionally, upcoming changes to the NICE methods review may help address uncertainties for histology-independent oncology products to optimise access.

PNS181 Exploring the Use of VALUE of Information Analysis in HTA Decision Making at Nice

Value of information analysis (VOI) is a quantitative method to estimate the expected value of additional research to reduce uncertainty in decision making. As part of the NICE methods review, we aimed to develop a VOI framework that could potentially help inform decision makers when considering the value of further evidence to reduce uncertainty in health technology assessment (HTA), and to explore barriers to implementing such a framework. A 2016 Decision Support Unit report considered the use of VOI when developing managed access agreements. Expanding on its principles, we developed a decision-making framework based on the expected value of perfect information (EVPI) and expected net benefit (NB) of approving a technology with current uncertainty, outlining scenarios where additional evidence to reduce uncertainty may add value. We evaluated the potential limitations of the framework and the practical implications of implementing it in a NICE setting. The outcomes of the framework depend on whether a technology is expected to be cost effective based on current evidence. If it is, further research may still be worthwhile if EVPI is higher than NB. Where a technology is expected to be cost ineffective, further research may be worthwhile if EVPI is higher than the expected NB loss of approval, otherwise a price reduction may be required. However, EVPI is an upper limit on the value of reducing parameter uncertainty. Less idealistic approaches are likely to estimate VOI more accurately but are more complex and require additional information (e.g. research design). Other considerations include the relevant time horizon, beneficiary population size and importance of uncertainties captured by VOI. A formal VOI framework may help HTA decision makers consider the suitability of recommending further research. Implementing the framework in a real-world HTA setting has methodological and practical challenges.

PRO89 The Use of EQ-5D in NICE Highly Specialised Technologies Evaluations: A Review of Published Guidance

EQ-5D is widely used in health technology assessments in a variety of conditions, but it is important to consider whether it is appropriate for ultra-rare diseases. This review examines the use of EQ-5D and other HRQoL measures in NICE highly specialised technologies (HST) evaluations and the committee’s conclusions on their appropriateness. Published HST evaluations were reviewed in February 2020, to inform the ongoing NICE methods review. Data extracted included disease area, population, EQ-5D data availability and whether they were collected in the clinical trials, other HRQoL measures presented, and committee’s conclusions about the appropriateness of EQ-5D and other measures. Twelve evaluations were reviewed. Results show that EQ-5D data were either collected in the trials (17%) or available from the literature (33%) in half of cases. In a quarter, other generic measures, such as the SF-36 or HUI3 (25%) were used instead of, or presented alongside, EQ-5D. Alternative methods were sometimes used to obtain EQ-5D values, such as clinicians completing EQ-5D for vignettes (33%) or using mapping algorithms to derive EQ-5D values from another measure (8%). The evaluation documents do not record any instances of the committee being presented with data to demonstrate EQ-5D being inappropriate (e.g. poor responsiveness or lack of validity). Where the committee did accept modelling based on alternative HRQoL measures, this was because there was no EQ-5D data available. In HST evaluations, lack of EQ-5D has been a bigger issue than concerns about its appropriateness. Where EQ-5D was not available, other HRQoL measures have informed committee’s decisions. Where EQ-5D was available, the committee often noted concerns about the methods used to derive the data and the robustness of the estimates. The challenges and uncertainties around measuring HRQoL in ultra-rare diseases are important for committees to consider but is not a barrier to decision-making.

PNS239 Working Towards Fewer Economic Orphans: Developing Nice Methods Guidance on Children's Health-Related Quality of Life

PNS239 Working Towards Fewer Economic Orphans: Developing Nice Methods Guidance on Children's Health-Related Quality of Life

Keeping Pace with Pharmaceutical Innovation: The Importance of the NICE Methods Review.

Keeping Pace with Pharmaceutical Innovation: The Importance of the NICE Methods Review.

Novel Enhancer for Luminol-AuNP Electrochemiluminescence and Decoration on RNA Membranes for Effective Cytosensing.

Herein, a simple and nice method to synthesize RNA membrane nanostructures for a controlled capture and cytosensing by aptamer and luminol-AuNPs (luAu NPs) is presented. The RNA membrane made up of many RNA transcripts was prepared by a one-pot reaction, the rolling circle transcription (RCT) process using rNTP and RNA polymerase, so the efficient RNA membrane could be obtained successfully at a much lower cost than the system used for RNA molecule synthesis commercially. The modifications of the NH2 group could not degrade the stability of RNA membrane in the serum. The prepared RNA membrane nanostructures showed interesting capture efficiencies toward the Ramos cell due to the effect of aptamer-ligand interactions on the nanostructures. Additionally, based on the detection of the luAu NP electrochemiluminescence (ECL) system, a novel enhancing method was employed by 3-aminopropyl-triethoxysilane (APS) for luAu NP ECL, which has never been reported, to improve the sensitivity. The ECL intensity was proportional to the target cell amounts, and the dynamic range was 50-5000 cells. The detection limit of the target cell amounts reached level 50. The specificity test and recovery test showed that the method had a good selectivity, stability, and repeatability. Therefore, this method will provide a favorable analysis for biosensing.

In-Motion Filter-QUEST Alignment for Strapdown Inertial Navigation Systems

By analyzing the error models of the measured vectors of the gravitational apparent motion, an in-motion filter-QUEST alignment method only with the inertial measurement unit is presented in this paper. The contribution of the proposed method lies in constructing the in-motion model of the measured vectors of the gravitational apparent motion and developing the extracted method to reconstruct the measured vectors. Furthermore, the relationship between the noise characteristic and the moving state of the vehicle is analyzed in detail. Different from the several current techniques, the presented method can be carried out without any other external additional equipment, when the vehicle is in-motion. With the designed real-time wavelet denoising (RWD) method, the high-frequency noises of the measured vectors are filtered. Based on the constructed parameter recognition model of the measured vectors, a robust adaptive Kalman filter is devised to estimate the optimal parameters, which are used to calculate the reconstructed observation vectors. Moreover, the gross outliers, which are contained in the filtered vectors of the RWD, are eliminated effectively. The simulation and the field trial results demonstrate that the presented method is applicable to the in-motion initial alignment, and it can serve as a nice initial alignment method in the follow-on fine alignment process and navigation process.

Heini Halberstam, 1926-2014

Heini Halberstam, 1926-2014

Breast cancer STAs becoming more compliant with NICE methods

Breast cancer STAs becoming more compliant with NICE methods