Is the assumption of waning of treatment effect applied consistently across NICE technology appraisals? A case-study focusing on disease-modifying therapies for treatment of multiple sclerosis.

OBJECTIVES: Whether the effects of therapies may wane over time is a matter of debate, especially when considering their long-term cost-effectiveness. Here, we examined how the assumption of the waning of treatment effect was applied across the National Institute for Health and Care Excellence (NICE) appraisals for disease-modifying therapies (DMTs) used in multiple sclerosis. METHODS: We undertook a document analysis following a search of the NICE website. The inclusion criteria of the study were as follows: all publicly available documents related to completed appraisals for DMTs (period: January 2000 to July 2021). The exclusion criteria of the study were as follows: all documents that did not meet the inclusion criteria, especially pertaining to drugs used in other disease areas. We extracted information about the waning of treatment effect assumption as considered by companies, assessment groups, and appraisal committees, and we analyzed trends over time. RESULTS: We reviewed fifteen appraisals that reported guidance on sixteen DMTs. Irrespective of the drugs' mechanism of action or their pharmaceutical nature, there was substantial variation in the modalities when the assumption of waning was implemented. We noted the recent preference to use all-cause discontinuation as a proxy. This heterogeneity did not appear to affect acceptance of the DMTs (all but one were recommended for use across the National Health System (NHS)). CONCLUSIONS: Modeling the long-term effect of therapies is challenging, especially given the limited follow-up duration of related trials. This generates recurrent debates on the presence of waning of treatment efficacy and heterogeneity across appraisals. More refined recommendations obtained by consensus among stakeholders could help to achieve greater consistency in decision making.

The Role of Prevention in Reducing the Economic Impact of ME/CFS in Europe: A Report from the Socioeconomics Working Group of the European Network on ME/CFS (EUROMENE).

This report addresses the extent to which there may be scope for preventive programmes for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), and, if so, what economic benefits may accrue from the implementation of such programmes. We consider the economic case for prevention programmes, whether there is scope for preventive programmes for ME/CFS, and what are the health and economic benefits to be derived from the implementation of such programmes. We conclude that there is little scope for primary prevention programmes, given that ME/CFS is attributable to a combination of host and environmental risk factors, with host factors appearing to be most prominent, and that there are few identified modifiable risk factors that could be the focus of such programmes. The exception is in the use of agricultural chemicals, particularly organophosphates, where there is scope for intervention, and where Europe-wide programmes of health education to encourage safe use would be beneficial. There is a need for more research on risk factors for ME/CFS to establish a basis for the development of primary prevention programmes, particularly in respect of occupational risk factors. Secondary prevention offers the greatest scope for intervention, to minimise diagnostic delays associated with prolonged illness, increased severity, and increased costs.

Perceptions of European ME/CFS Experts Concerning Knowledge and Understanding of ME/CFS among Primary Care Physicians in Europe: A Report from the European ME/CFS Research Network (EUROMENE).

Background and Objectives: We have conducted a survey of academic and clinical experts who are participants in the European ME/CFS Research Network (EUROMENE) to elicit perceptions of general practitioner (GP) knowledge and understanding of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and suggestions as to how this could be improved. Materials and Methods: A questionnaire was sent to all national representatives and members of the EUROMENE Core Group and Management Committee. Survey responses were collated and then summarized based on the numbers and percentages of respondents selecting each response option, while weighted average responses were calculated for questions with numerical value response options. Free text responses were analysed using thematic analysis. Results: Overall there were 23 responses to the survey from participants across 19 different European countries, with a 95% country-level response rate. Serious concerns were expressed about GPs' knowledge and understanding of ME/CFS, and, it was felt, about 60% of patients with ME/CFS went undiagnosed as a result. The vast majority of GPs were perceived to lack confidence in either diagnosing or managing the condition. Disbelief, and misleading illness attributions, were perceived to be widespread, and the unavailability of specialist centres to which GPs could refer patients and seek advice and support was frequently commented upon. There was widespread support for more training on ME/CFS at both undergraduate and postgraduate levels. Conclusion: The results of this survey are consistent with the existing scientific literature. ME/CFS experts report that lack of knowledge and understanding of ME/CFS among GPs is a major cause of missed and delayed diagnoses, which renders problematic attempts to determine the incidence and prevalence of the disease, and to measure its economic impact. It also contributes to the burden of disease through mismanagement in its early stages.

A Literature Review of GP Knowledge and Understanding of ME/CFS: A Report from the Socioeconomic Working Group of the European Network on ME/CFS (EUROMENE).

Background and Objectives: The socioeconomic working group of the European myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) Research Network (EUROMENE) has conducted a review of the literature pertaining to GPs' knowledge and understanding of ME/CFS; Materials and Methods: A MEDLINE search was carried out. The papers identified were reviewed following the synthesis without meta-analysis (SWiM) methodology, and were classified according to the focus of the enquiry (patients, GPs, database and medical record studies, evaluation of a training programme, and overview papers), and whether they were quantitative or qualitative in nature; Results: Thirty-three papers were identified in the MEDLINE search. The quantitative surveys of GPs demonstrated that a third to a half of all GPs did not accept ME/CFS as a genuine clinical entity and, even when they did, they lacked confidence in diagnosing or managing it. It should be noted, though, that these papers were mostly from the United Kingdom. Patient surveys indicated that a similar proportion of patients was dissatisfied with the primary medical care they had received. These findings were consistent with the findings of the qualitative studies that were examined, and have changed little over several decades; Conclusions: Disbelief and lack of knowledge and understanding of ME/CFS among GPs is widespread, and the resultant diagnostic delays constitute a risk factor for severe and prolonged disease. Failure to diagnose ME/CFS renders problematic attempts to determine its prevalence, and hence its economic impact.

Health economic evaluation of strategies to eliminate gambiense human African trypanosomiasis in the Mandoul disease focus of Chad.

Human African trypanosomiasis, caused by the gambiense subspecies of Trypanosoma brucei (gHAT), is a deadly parasitic disease transmitted by tsetse. Partners worldwide have stepped up efforts to eliminate the disease, and the Chadian government has focused on the previously high-prevalence setting of Mandoul. In this study, we evaluate the economic efficiency of the intensified strategy that was put in place in 2014 aimed at interrupting the transmission of gHAT, and we make recommendations on the best way forward based on both epidemiological projections and cost-effectiveness. In our analysis, we use a dynamic transmission model fit to epidemiological data from Mandoul to evaluate the cost-effectiveness of combinations of active screening, improved passive screening (defined as an expansion of the number of health posts capable of screening for gHAT), and vector control activities (the deployment of Tiny Targets to control the tsetse vector). For cost-effectiveness analyses, our primary outcome is disease burden, denominated in disability-adjusted life-years (DALYs), and costs, denominated in 2020 US$. Although active and passive screening have enabled more rapid diagnosis and accessible treatment in Mandoul, the addition of vector control provided good value-for-money (at less than $750/DALY averted) which substantially increased the probability of reaching the 2030 elimination target for gHAT as set by the World Health Organization. Our transmission modelling and economic evaluation suggest that the gains that have been made could be maintained by passive screening. Our analysis speaks to comparative efficiency, and it does not take into account all possible considerations; for instance, any cessation of ongoing active screening should first consider that substantial surveillance activities will be critical to verify the elimination of transmission and to protect against the possible importation of infection from neighbouring endemic foci.

The Development of a Consistent Europe-Wide Approach to Investigating the Economic Impact of Myalgic Encephalomyelitis (ME/CFS): A Report from the European Network on ME/CFS (EUROMENE).

We have developed a Europe-wide approach to investigating the economic impact of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), facilitating acquisition of information on the economic burden of ME/CFS, and international comparisons of economic costs between countries. The economic burden of ME/CFS in Europe appears large, with productivity losses most significant, giving scope for substantial savings through effective prevention and treatment. However, economic studies of ME/CFS, including cost-of-illness analyses and economic evaluations of interventions, are problematic due to different, arbitrary case definitions, and unwillingness of doctors to diagnose it. We therefore lack accurate incidence and prevalence data, with no obvious way to estimate costs incurred by undiagnosed patients. Other problems include, as for other conditions, difficulties estimating direct and indirect costs incurred by healthcare systems, patients and families, and heterogeneous healthcare systems and patterns of economic development across countries. We have made recommendations, including use of the Fukuda (CDC-1994) case definition and Canadian Consensus Criteria (CCC), a pan-European common symptom checklist, and implementation of prevalence-based cost-of-illness studies in different countries using an agreed data list. We recommend using purchasing power parities (PPP) to facilitate international comparisons, and EuroQol-5D as a generic measure of health status and multi-attribute utility instrument to inform future economic evaluations in ME/CFS.

Systematic Review of the Epidemiological Burden of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Across Europe: Current Evidence and EUROMENE Research Recommendations for Epidemiology.

This review aimed at determining the prevalence and incidence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in Europe. We conducted a primary search in Scopus, PubMed and Web of Science for publications between 1994 and 15 June 2019 (PROSPERO: CRD42017078688). Additionally, we performed a backward-(reference lists) and forward-(citations) search of the works included in this review. Grey literature was addressed by contacting all members of the European Network on ME/CFS (EUROMENE). Independent reviewers searched, screened and selected studies, extracted data and evaluated the methodological and reporting quality. For prevalence, two studies in adults and one study in adolescents were included. Prevalence ranged from 0.1% to 2.2%. Two studies also included incidence estimates. In conclusion, studies on the prevalence and incidence of ME/CFS in Europe were scarce. Our findings point to the pressing need for well-designed and statistically powered epidemiological studies. To overcome the shortcomings of the current state-of-the-art, EUROMENE recommends that future research is better conducted in the community, reviewing the clinical history of potential cases, obtaining additional objective information (when needed) and using adequate ME/CFS case definitions; namely, the Centers for Disease Control & Prevention-1994, Canadian Consensus Criteria, or Institute of Medicine criteria.