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Background Missing data are common in randomised controlled trials (RCTs) and can bias results if not handled appropriately. A statistically valid analysis under the primary missing-data assumptions should be conducted, followed by sensitivity analysis under alternative justified assumptions to assess the robustness of results. Controlled Multiple Imputation (MI) procedures, including delta-based and reference-based approaches, have been developed for analysis under missing-not-at-random assumptions. However, it is unclear how often these methods are used, how they are reported, and what their impact is on trial results. This review evaluates the current use and reporting of MI and controlled MI in RCTs. Methods A targeted review of phase II-IV RCTs (non-cluster randomised) published in two leading general medical journals (The Lancet and New England Journal of Medicine) between January 2014 and December 2019 using MI. Data was extracted on imputation methods, analysis status, and reporting of results. Results of primary and sensitivity analyses for trials using controlled MI analyses were compared. Results A total of 118 RCTs (9% of published RCTs) used some form of MI. MI under missing-at-random was used in 110 trials; this was for primary analysis in 43/118 (36%), and in sensitivity analysis for 70/118 (59%) (3 used in both). Sixteen studies performed controlled MI (1.3% of published RCTs), either with a delta-based ( n  = 9) or reference-based approach ( n  = 7). Controlled MI was mostly used in sensitivity analysis ( n  = 14/16). Two trials used controlled MI for primary analysis, including one reporting no sensitivity analysis whilst the other reported similar results without imputation. Of the 14 trials using controlled MI in sensitivity analysis, 12 yielded comparable results to the primary analysis whereas 2 demonstrated contradicting results. Only 5/110 (5%) trials using missing-at-random MI and 5/16 (31%) trials using controlled MI reported complete details on MI methods. Conclusions Controlled MI enabled the impact of accessible contextually relevant missing data assumptions to be examined on trial results. The use of controlled MI is increasing but is still infrequent and poorly reported where used. There is a need for improved reporting on the implementation of MI analyses and choice of controlled MI parameters.

To assess the comparative efficacy of short-acting muscarinic antagonists (SAMAs), long-acting muscarinic antagonists (LAMAs), LAMA in combination with long-acting beta-agonists (LABAs; LAMA/LABAs) and inhaled corticosteroids (ICS) in combination with LABA (ICS/LABAs) for the maintenance treatment of COPD. We systematically reviewed 74 randomized controlled trials (74,832 participants) published up to 15 November 2017, which compared any of the interventions (SAMA [ipratropium], LAMA [aclidinium, glycopyrronium, tiotropium, umeclidinium], LAMA/LABA [aclidinium/formoterol, indacaterol/glycopyrronium, tiotropium/olodaterol, umeclidinium/vilanterol] and ICS/LABA [fluticasone/vilanterol, budesonide/formoterol, salmeterol/fluticasone]) with each other or with placebo. A random-effects network meta-analysis combining direct and indirect evidence was conducted to examine the change from baseline in trough FEV , transition dyspnea index, St George's Respiratory Questionnaire and frequency of adverse events at weeks 12 and 24. Inconsistency models were not statistically significant for all outcomes. LAMAs, LAMA/LABAs and ICS/LABAs led to a significantly greater improvement in trough FEV compared with placebo and SAMA monotherapy at weeks 12 and 24. All LAMA/LABAs, except aclidinium/formoterol, were statistically significantly better than LAMA monotherapy and ICS/LABAs in improving trough FEV . Among the LAMAs, umeclidinium showed statistically significant improvement in trough FEV at week 12 compared to tiotropium and glycopyrronium, but the results were not clinically significant. LAMA/LABAs had the highest probabilities of being ranked the best agents in FEV improvement. Similar trends were observed for the transition dyspnea index and St George's Respiratory Questionnaire outcomes. There were no significant differences in the incidences of adverse events among all treatment options. LAMA/LABA showed the greatest improvement in trough FEV at weeks 12 and 24 compared with the other inhaled drug classes, while SAMA showed the least improvement. There were no significant differences among the LAMAs and LAMA/LABAs within their respective classes.

Background Non-small-cell lung cancer (NSCLC) accounts for 85% of all lung cancers and is associated with a poor prognosis. Afatinib is an irreversible ErbB family blocker recommended in clinical guidelines as a first-line treatment for NSCLC which harbours an epidermal growth factor receptor (EGFR) mutation. The objective of this study was to evaluate the cost-effectiveness of afatinib versus pemetrexed-cisplatin for first-line treatment of locally advanced or metastatic EGFR mutation positive NSCLC in Singapore. Methods A partitioned survival model with three health states (progression-free, progressive disease and death) was developed from a healthcare payer perspective. Survival curves from the LUX-Lung 3 trial (afatinib versus pemetrexed-cisplatin chemotherapy) were extrapolated beyond the trial period to estimate the underlying progression-free survival and overall survival parametric distributions. Rates of adverse reactions were also estimated from LUX-Lung 3 while health utilities from overseas were derived from the literature in the absence of local estimates. Direct costs were sourced from public healthcare institutions in Singapore. Incremental cost-effectiveness ratios (ICERs) were calculated over a 5 year time horizon. Deterministic and probabilistic sensitivity analyses and additional scenario analyses were conducted to explore the impact of uncertainties and assumptions on the cost-effectiveness results. Results In the base-case analysis, the ICER for afatinib versus pemetrexed-cisplatin was SG$137,648 per quality-adjusted life year (QALY) gained and SG$109,172 per life-year gained. One-way sensitivity analysis showed the ICER was most sensitive to variations in the utility values, the cost of afatinib and time horizon. Scenario analyses showed that even reducing the cost of afatinib by 50% led to a high ICER which was unlikely to represent a cost-effective use of healthcare resources. Conclusions Compared with pemetrexed-cisplatin, afatinib is not cost-effective as a first-line treatment for advanced EGFR mutation-positive NSCLC in Singapore. The findings from our study will be useful to inform local healthcare decision-making and resource allocations for NSCLC treatments, together with other considerations such as clinical effectiveness, safety and affordability of TKIs.

IntroductionIn 2022, the Agency for Care Effectiveness (ACE) co-developed patient involvement processes with local patient organizations to enable patients and caregivers to share their experiential knowledge about different medical conditions and treatments to inform health technology assessments (HTAs). This presentation describes the impact of patient input on funding recommendations during the first two years of this initiative in Singapore.MethodsA literature search was conducted to identify frameworks and indicators used by different HTA agencies that could be contextualized to evaluate local patient involvement efforts. Systematic data extraction was performed by two authors to compare patient testimonials received for HTAs conducted between May 2022 and April 2024 with key information in HTA reports, minutes from committee meetings, and published HTA guidance documents to determine the impact of patient and caregiver involvement on the committees’ deliberations and subsequent funding recommendations. The impact of patient involvement on ACE staff, existing processes, and patient participation in future HTAs was also assessed through qualitative surveys.ResultsIn the first year (May 2022 to April 2023), 112 patient responses informed 11 HTAs, while 243 responses informed 16 HTAs in the subsequent year (May 2023 to April 2024). At least one testimonial was received for 84.6 percent of HTAs in the first year, increasing to 88.9 percent in the subsequent year. Patient input addressed uncertainties in the scientific evidence and helped decision-making committees understand how different conditions affect patients and their caregivers, the outcomes that matter most to patients, and the benefits and disadvantages of different treatments. In response to feedback, ACE continually evolved its processes to meet the needs of patients and to encourage broader patient participation. Industry and patient organizations also expanded their capacity so that they can meaningfully participate in future ACE HTAs.ConclusionsContinuous process improvement in response to feedback; providing patient input templates in different formats and languages to improve accessibility; and regular feedback to patient organizations on how their inputs have informed HTAs have increased patient participation, improved the legitimacy of ACE HTAs, and added value to decision-making about which health technologies should be funded in Singapore.

IntroductionIn Singapore, health technologies were previously identified for funding consideration through horizon scanning or annual applications from clinicians, before being prioritized by the Ministry of Health advisory committees for evaluation by the Agency for Care Effectiveness (ACE). This poster describes a new process co-developed with local patient organizations to enable patients and caregivers to suggest health technologies for evaluation.MethodsAn application form was developed in plain language for patients and caregivers which requested the name of the health technology and its formulation, the medical condition it is used for, the perceived benefits and disadvantages, and the reasons why it should be funded. A factsheet explaining the selection process was codeveloped with patients, published online, and sent electronically with the application form in October 2023 to all local patient organizations, alongside the open application call for clinicians. Applications were accepted until January 2024 and then collated for prioritization in line with predefined selection criteria. All patients were notified of the outcome of their application.ResultsFifty applications were received from patients during the first two months of the open call compared to 75 from clinicians. Most of the patient applications (66%) requested drugs for treating asthma or respiratory conditions. Drugs requested by clinicians generally differed from those requested by patients except for 5 topics, suggesting that patients may perceive clinical need differently. Most patient applicants had used the requested drugs before and considered they were effective and convenient, but unaffordable. Health technologies were more likely to be prioritized for evaluation when their benefits were plausible and supported by evidence, and they could fill an unmet clinical need for patients.ConclusionsThe process will be updated in line with feedback to encourage continued patient participation annually. Enabling patients and caregivers to suggest health technologies for evaluation provides ACE with a better understanding of their needs, preferences, lived experiences, and expectations, and ensures that subsequent funding recommendations informed by ACE’s evaluations address therapeutic gaps and improve treatment affordability and patient outcomes.

IntroductionPatient involvement in health technology assessment (HTA) at the organizational level is vital to drive process development and capacity-building, and to ensure patients have the same opportunities as other stakeholders to effect policy changes. This presentation discusses the role and impact of the Agency for Care Effectiveness (ACE) Consumer Panel in the co-development of patient involvement and education initiatives in Singapore.MethodsThe composition and terms of reference of patient and citizen groups in overseas HTA or government agencies were reviewed to identify key aspects that could be generalized to Singapore’s context. Using selection criteria, 20 individuals from local patient or voluntary groups representing a broad range of health conditions were shortlisted; 15 were formally appointed to the Panel in April 2022. Their contributions and impact on ACE’s work and healthcare decision-making were documented throughout their two-year term. A qualitative survey was also conducted to seek members’ feedback on their participation in the Panel and identify areas to improve collaboration.ResultsSince their appointment, ACE Consumer Panel members have played a key role in providing the collective voice of local patient organizations to guide ACE’s work and have co-developed processes that ensure meaningful patient involvement in policy development and HTA. They have also informed ACE’s workplan by providing advice on priority-setting, communication strategies, and patients’ information needs. During their term, processes to include patient input in HTAs were formalized leading to the co-development of a process guide and supporting fact sheets, a patient glossary, and two patient training modules, which will be continually updated based on patient feedback.ConclusionsThe ACE Consumer Panel is the first long-standing engagement of healthcare consumers by Singapore’s Ministry of Health. The Panel’s contributions and impact on ACE’s work serve as an example for other decision-makers on how to meaningfully involve patients at the organizational level, to understand their priorities and preferences, and to ensure healthcare policies remain relevant for the people affected by them.

IntroductionPatient involvement has become increasingly integral to health technology assessment (HTA) processes globally due to greater recognition of the important contribution patients make to address uncertainties in the scientific evidence base and interpret results for real-world implementation. To align with best practices and encourage meaningful patient input in HTAs in Singapore, patient involvement processes were established by the Agency for Care Effectiveness (ACE) in 2021. This presentation discusses how patient groups were identified in Singapore and describes the new patient involvement processes.MethodsIn the absence of a centralized database, a stakeholder mapping exercise was undertaken in 2021 to identify all relevant patient and volunteer groups in Singapore. A comprehensive search of the Singapore Charity Portal, hospital websites, standard search engines and social media platforms was conducted.Identified groups were screened in line with specific inclusion criteria and contacted via email and cold calling to find out more about their remits. Plain English resources, targeted training materials and a process guide to encourage patient involvement in ACE’s work were co-developed with local patient organizations by drawing upon best practices from overseas HTA agencies contextualized to local patients’ needs. Supporting resources and processes were revised in 2022 based on ACE’s experience receiving inputs from patients and caregivers to inform drug HTAs.ResultsOne hundred and six patient groups covering 20 conditions were identified including registered organizations and informal support groups. In the first half of 2022, ACE received responses from 82 patients from ten patient organizations to inform seven drug HTAs for cancer, diabetes, HIV, and other conditions in line with the new patient involvement processes. Patient organizations viewed the opportunity to submit testimonials of their lived experience with different conditions as a meaningful and important activity for their members.ConclusionsPatient involvement processes have improved the legitimacy and acceptance of ACE’s work and will be continuously revised to ensure that they remain relevant and meet patients’ expectations and needs.

Background The coronavirus disease 2019 (COVID-19) pandemic has caused significant psychological distress globally. Our study assessed the prevalence of psychological distress and associated factors during COVID-19 pandemic among kidney transplant recipients and kidney donors. Methods A cross-sectional survey of 497 participants (325 recipients and 172 donors) was conducted from 1st May to 30th June 2020 in Singapore. The survey questionnaire assessed knowledge levels of COVID-19, socio-demographic data, health status, psychosocial impact of COVID-19, and precautionary behaviors during the pandemic. Psychological distress was defined as having anxiety, depression, or stress measured by the validated Depression, Anxiety and Stress Scale-21. Linear regression analyses were used to assess factors associated with higher psychological distress. Results The prevalence of psychological distress was 14.3% (95% confidence interval: 11.5–17.6%) in the overall population; it was 12.8% (9.79–16.6%) in recipients and 13.4% (9.08–19.6%) in donors with no significant difference ( P  = 0.67). Younger age (21–49 vs. ≥50 years), unmarried status, non-Singapore citizen, worse health conditions, and worrying about physical and mental health were associated with higher psychological distress. Malays (versus Chinese), taking precautionary measures (hand sanitization), and receiving enough information about COVID-19 were associated with lower psychological distress. No interactions were observed between recipients and donors. Conclusions At least one in ten recipients and donors suffer from psychological distress during COVID-19 pandemic . Focused health education to younger adults, unmarried individuals, non-Singapore citizens, and those with poor health status could potentially prevent psychological distress in recipients and donors.

Cardiovascular disease (CVD) is the leading cause of death in many countries. Hypercholesterolaemia is a recurring risk factor in CVD leading to coronary atherosclerosis, stroke and ischemic heart disease. Previous research has proven that seaweeds are highly nutritious, providing a good source of dietary fibre, minerals, proteins and vitamins as well as being high in antioxidants. Antioxidants have been known to retard low-density lipoprotein (LDL) oxidation to reduce CVD risk in hypercholesterolaemia. However, there is yet to be a study on the effect of a mixture of different seaweed species on cholesterol lowering properties. Therefore, this study was designed to investigate the effects of a mixture of extracts from two seaweed species, red seaweed Kappaphycus alvarezii and brown seaweed Sargassum polycystum on plasma lipid and antioxidant profiles of rats fed high-cholesterol diet. S. polycystum extract significantly decreased plasma cholesterol by 37.52 % over an 8-week treatment period compared to K. alvarezii and mixture groups. However, S. polycystum showed an increase in plasma triglyceride (TG) levels by 16.66 %. K. alvarezii extract most effectively decreased TG levels by 40.11 % and the mixture extract most effectively increased high-density lipoprotein cholesterol by 56.71 %. All treatment groups were able to reduce LDL cholesterol levels compared to the high-cholesterol group, with no significant differences between them. K. alvarezii and S. polycystum mixture extract had the best atherogenic index, which is an indicator of lipid disorder in coronary diseases, among treatment and high-cholesterol-fed groups. All treatment groups were able to restore enzyme antioxidant levels (superoxide dismutase and catalase) to normal.