Challenges and Opportunities in Interdisciplinary Research and Real-World Data for Treatment Sequences in Health Technology Assessments.

With an ever-increasing number of treatment options, the assessment of treatment sequences has become crucial in health technology assessment (HTA). This review systematically explores the multifaceted challenges inherent in evaluating sequences, delving into their interplay and nuances that go beyond economic model structures. We synthesised a 'roadmap' of literature from key methodological studies, highlighting the evolution of recent advances and emerging research themes. These insights were compared against HTA guidelines to identify potential avenues for future research. Our findings reveal a spectrum of challenges in sequence evaluation, encompassing selecting appropriate decision-analytic modelling approaches and comparators, deriving appropriate clinical effectiveness evidence in the face of data scarcity, scrutinising effectiveness assumptions and statistical adjustments, considering treatment displacement, and optimising model computations. Integrating methodologies from diverse disciplines-statistics, epidemiology, causal inference, operational research and computer science-has demonstrated promise in addressing these challenges. An updated review of application studies is warranted to provide detailed insights into the extent and manner in which these methodologies have been implemented. Data scarcity on the effectiveness of treatment sequences emerged as a dominant concern, especially because treatment sequences are rarely compared in clinical trials. Real-world data (RWD) provide an alternative means for capturing evidence on effectiveness and future research should prioritise harnessing causal inference methods, particularly Target Trial Emulation, to evaluate treatment sequence effectiveness using RWD. This approach is also adaptable for analysing trials harbouring sequencing information and adjusting indirect comparisons when collating evidence from heterogeneous sources. Such investigative efforts could lend support to reviews of HTA recommendations and contribute to synthesising external control arms involving treatment sequences.

Diagnostic accuracy of conventional oral examination for detecting oral cavity cancer and potentially malignant disorders in patients with clinically evident oral lesions: Systematic review and meta-analysis.

This systematic review evaluates the diagnostic accuracy of conventional oral examination (COE) versus incisional or excisional biopsy for the diagnosis of malignant and/or dysplastic lesions in patients with clinically evident lesions. Searches were conducted across five electronic databases from inception to January 2020. Meta-analyses were undertaken, where appropriate. Among 18 included studies, 14 studies were included in the meta-analysis, giving summary estimates for COE of 71% sensitivity and 85% specificity for the diagnosis of dysplastic and/or malignant lesions. The pooled diagnostic accuracy of identifying malignant-only lesions was reported in seven studies, giving a pooled estimate of 88% sensitivity and 81% specificity. Diagnostic accuracy of different types of dental/medical professionals in identifying dysplastic or malignant lesions gave varying estimates of sensitivity and specificity across three studies. Further research is needed to improve the diagnostic accuracy of COE for early detection of dysplastic and malignant oral lesions.

External Validation of a Colorectal Cancer Model Against Screening Trial Long-Term Follow-Up Data.

BACKGROUND: The University of Sheffield School of Health and Related Research (ScHARR) Bowel Cancer Screening Model has been used previously to make decisions about colorectal cancer screening strategies in England. OBJECTIVES: The objective of this study was to perform an external validation of the ScHARR model against long-term follow-up data about colorectal cancer (CRC) incidence and mortality reductions due to screening, from the Nottingham trial of guaiac faecal occult blood testing for CRC, and the UK Flexible Sigmoidoscopy Screening Trial. METHODS: The ScHARR model was adapted prior to validation to reflect the setting of each trial in terms of population characteristics, details of screening and surveillance programs, uptake of screening, and further investigations and study follow-up. The impact of using current versus historical CRC incidence and mortality data in the validation was also examined by carrying out a series of analyses in which historical data from different years was included in the model. RESULTS: The ScHARR model was able to predict CRC incidence and mortality rate/hazard ratios from both trials to well within the 95% confidence intervals in the observed data. While it was less accurate in predicting absolute incidence and mortality rates, modeling historical incidence and mortality data enabled these predictions to be improved considerably. CONCLUSION: The ScHARR model is able to replicate the long-term relative benefit from screening observed in 2 large-scale UK-based screening trials and can therefore be considered to be an appropriate tool to facilitate decision making around the English bowel cancer screening program.

Economic impact of screening for X-linked Adrenoleukodystrophy within a newborn blood spot screening programme.

BACKGROUND: A decision tree model was built to estimate the economic impact of introducing screening for X-linked adrenoleukodystrophy (X-ALD) into an existing tandem mass spectrometry based newborn screening programme. The model was based upon the UK National Health Service (NHS) Newborn Blood Spot Screening Programme and a public service perspective was used with a lifetime horizon. The model structure and parameterisation were based upon literature reviews and expert clinical judgment. Outcomes included health, social care and education costs and quality adjusted life years (QALYs). The model assessed screening of boys only and evaluated the impact of improved outcomes from hematopoietic stem cell transplantation in patients with cerebral childhood X-ALD (CCALD). Threshold analyses were used to examine the potential impact of utility decrements for non-CCALD patients identified by screening. RESULTS: It is estimated that screening 780,000 newborns annually will identify 18 (95%CI 12, 27) boys with X-ALD, of whom 10 (95% CI 6, 15) will develop CCALD. It is estimated that screening may detect 7 (95% CI 3, 12) children with other peroxisomal disorders who may also have arisen symptomatically. If results for girls are returned an additional 17 (95% CI 12, 25) cases of X-ALD will be identified. The programme is estimated to cost an additional £402,000 (95% CI £399-407,000) with savings in lifetime health, social care and education costs leading to an overall discounted cost saving of £3.04 (95% CI £5.69, £1.19) million per year. Patients with CCALD are estimated to gain 8.5 discounted QALYs each giving an overall programme benefit of 82 (95% CI 43, 139) QALYs. CONCLUSION: Including screening of boys for X-ALD into an existing tandem mass spectrometry based newborn screening programme is projected to reduce lifetime costs and improve outcomes for those with CCALD. The potential disbenefit to those identified with non-CCALD conditions would need to be substantial in order to outweigh the benefit to those with CCALD. Further evidence is required on the potential QALY impact of early diagnosis both for non-CCALD X-ALD and other peroxisomal disorders. The favourable economic results are driven by estimated reductions in the social care and education costs.

COMPREHENSIVE ASSESSMENT OF COMPLEX TECHNOLOGIES: INTEGRATING VARIOUS ASPECTS IN HEALTH TECHNOLOGY ASSESSMENT.

OBJECTIVES: Despite recent development of health technology assessment (HTA) methods, there are still methodological gaps for the assessment of complex health technologies. The INTEGRATE-HTA guidance for effectiveness, economic, ethical, socio-cultural, and legal aspects, deals with challenges when assessing complex technologies, such as heterogeneous study designs, multiple stakeholder perspectives, and unpredictable outcomes. The objective of this article is to outline this guidance and describe the added value of integrating these assessment aspects. METHODS: Different methods were used to develop the various parts of the guidance, but all draw on existing, published knowledge and were supported by stakeholder involvement. The guidance was modified after application in a case study and in response to feedback from internal and external reviewers. RESULTS: The guidance consists of five parts, addressing five core aspects of HTA, all presenting stepwise approaches based on the assessment of complexity, context, and stakeholder involvement. The guidance on effectiveness, health economics and ethics aspects focus on helping users choose appropriate, or further develop, existing methods. The recommendations are based on existing methods' applicability for dealing with problems arising with complex interventions. The guidance offers new frameworks to identify socio-cultural and legal issues, along with overviews of relevant methods and sources. CONCLUSIONS: The INTEGRATE-HTA guidance outlines a wide range of methods and facilitates appropriate choices among them. The guidance enables understanding of how complexity matters for HTA and brings together assessments from disciplines, such as epidemiology, economics, ethics, law, and social theory. This indicates relevance for a broad range of technologies.

Avoiding and identifying errors and other threats to the credibility of health economic models.

Health economic models have become the primary vehicle for undertaking economic evaluation and are used in various healthcare jurisdictions across the world to inform decisions about the use of new and existing health technologies. Models are required because a single source of evidence, such as a randomised controlled trial, is rarely sufficient to provide all relevant information about the expected costs and health consequences of all competing decision alternatives. Whilst models are used to synthesise all relevant evidence, they also contain assumptions, abstractions and simplifications. By their very nature, all models are therefore 'wrong'. As such, the interpretation of estimates of the cost effectiveness of health technologies requires careful judgements about the degree of confidence that can be placed in the models from which they are drawn. The presence of a single error or inappropriate judgement within a model may lead to inappropriate decisions, an inefficient allocation of healthcare resources and ultimately suboptimal outcomes for patients. This paper sets out a taxonomy of threats to the credibility of health economic models. The taxonomy segregates threats to model credibility into three broad categories: (i) unequivocal errors, (ii) violations, and (iii) matters of judgement; and maps these across the main elements of the model development process. These three categories are defined according to the existence of criteria for judging correctness, the degree of force with which such criteria can be applied, and the means by which these credibility threats can be handled. A range of suggested processes and techniques for avoiding and identifying these threats is put forward with the intention of prospectively improving the credibility of models.

The Multiple Sclerosis Risk Sharing Scheme Monitoring Study--early results and lessons for the future.

BACKGROUND: Risk sharing schemes represent an innovative and important approach to the problems of rationing and achieving cost-effectiveness in high cost or controversial health interventions. This study aimed to assess the feasibility of risk sharing schemes, looking at long term clinical outcomes, to determine the price at which high cost treatments would be acceptable to the NHS. METHODS: This case study of the first NHS risk sharing scheme, a long term prospective cohort study of beta interferon and glatiramer acetate in multiple sclerosis (MS) patients in 71 specialist MS centres in UK NHS hospitals, recruited adults with relapsing forms of MS, meeting Association of British Neurologists (ABN) criteria for disease modifying therapy. Outcome measures were: success of recruitment and follow up over the first three years, analysis of baseline and initial follow up data and the prospect of estimating the long term cost-effectiveness of these treatments. RESULTS: Centres consented 5560 patients. Of the 4240 patients who had been in the study for a least one year, annual review data were available for 3730 (88.0%). Of the patients who had been in the study for at least two years and three years, subsequent annual review data were available for 2055 (78.5%) and 265 (71.8%) patients respectively. Baseline characteristics and a small but statistically significant progression of disease were similar to those reported in previous pivotal studies. CONCLUSION: Successful recruitment, follow up and early data analysis suggest that risk sharing schemes should be able to deliver their objectives. However, important issues of analysis, and political and commercial conflicts of interest still need to be addressed.

Use of expert knowledge in evaluating costs and benefits of alternative service provisions: a case study.

OBJECTIVES: A treatment pathway model was developed to examine the costs and benefits of the current bowel cancer service in England and to evaluate potential alternatives in service provision. To use the pathway model, various parameters and probability distributions had to be specified. They could not all be determined from empirical evidence and, instead, expert opinion was elicited in the form of statistical quantities that gave the required information. The purpose of this study is to describe the procedures used to quantify expert opinion and note examples of good practice contained in the case study. METHODS: The required information was identified and preparatory discussion with four experts refined the questions they would be asked. In individual elicitation sessions they quantified their opinions, mainly in the form of point and interval estimates for specified variables. New methods have been developed for quantifying expert opinion and these were implemented in specialized software that uses interactive graphics. This software was used to elicit opinion about quantities related to measurable covariates. RESULTS: Assessments for thirty-four quantities were elicited and available checks supported their validity. Eight points of good practice in eliciting and using expert judgment were evident. Parameters and probability distributions needed for the pathway model were determined from the elicited assessments. Simulation results from the pathway model were used to inform policy on bowel cancer service provision. CONCLUSIONS: The study illustrates that quantifying and using expert judgment can be acceptable in real problems of practical importance. For full benefit to be gained from expert knowledge, elicitation must be conducted carefully and should be reported in detail.

Economic implications of the use of basiliximab in addition to triple immunosuppressive therapy in renal allograft recipients: a UK perspective.

OBJECTIVE: To compare resource use and costs in renal transplant recipients treated with basiliximab or placebo plus triple immunosuppressive therapy. DESIGN: International randomised, double-blind, placebo-controlled trial; economic evaluation undertaken alongside the efficacy trial. The economic evaluation was performed from a UK National Health Service hospital perspective. SETTING: 31 centres in 12 countries. PARTICIPANTS: 345 renal transplant recipients were enrolled; 340 were randomised (basiliximab 168; placebo 172) and included in the intention-to-treat analysis. INTERVENTION: Treatment with placebo or basiliximab (20mg intravenous bolus) on day 0 and day 4 after transplantation. MAIN OUTCOME MEASURES: Resource utilisation in multiple categories and treatment costs for basiliximab and placebo-treated patients during the 6-month post-transplantation period. RESULTS: No statistically significant differences were found in any of the economically important categories of resource use or in the mean cost of treatment per person across the whole trial. The mean cost of treatment, including the cost of basiliximab, was pound 16 095 for basiliximab recipients and pound 15 864 (1997/1998 costs) for placebo recipients, a mean difference of pound 231 (95% CI: - pound 1983 to pound 2446), which was not significant. Basiliximab treatment led to a significant reduction in acute rejection episodes (basiliximab 20.8%; placebo 34.9%; p = 0.005). CONCLUSIONS: Basiliximab therapy confers a significant clinical benefit to renal transplant recipients without increasing overall treatment costs.

The economics of basiliximab (Simulect) in preventing acute rejection in renal transplantation.

An economic evaluation was undertaken alongside a multicentre international trial of basiliximab. Resource usage within the trial was assessed, and the cost implications of using basiliximab evaluated. Recipients of a primary cadaveric kidney transplant were recruited into a double-blind trial and received either placebo ( n=186) or basiliximab ( n=190). Clinical outcomes and resource usage were monitored in the 12 months following transplantation. Local unit costs were obtained, and global analysis was undertaken using health sector purchasing-power parity rates. No statistically significant differences were found in the mean cost of treatment per patient. The mean cost of treatment was US$47,940 for basiliximab patients and US$46,280 for placebo patients, a mean difference of US$1,660 (95% confidence interval (CI): -US$4,150, US$7,360; P=0.58). Basiliximab produces clinical benefit in terms of preventing episodes of acute rejection, whilst the difference in the total resource usage and cost of treatment is not statistically significant.