What, Where, and How to Collect Real-World Data and Generate Real-World Evidence to Support Drug Reimbursement Decision-Making in Asia: A reflection Into the Past and A Way Forward.

BACKGROUND: Globally, there is increasing interest in the use of real-world data (RWD) and real-world evidence (RWE) to inform health technology assessment (HTA) and reimbursement decision-making. Using current practices and case studies shared by eleven health systems in Asia, a non-binding guidance that seeks to align practices for generating and using RWD/RWE for decision-making in Asia was developed by the REAL World Data In ASia for HEalth Technology Assessment in Reimbursement (REALISE) Working Group, addressing a current gap and needs among HTA users and generators. METHODS: The guidance document was developed over two face-to-face workshops, in addition to an online survey, a face-to-face interview and pragmatic search of literature. The specific focus was on what, where and how to collect RWD/ RWE. RESULTS: All 11 REALISE member jurisdictions participated in the online survey and the first in-person workshop, 10 participated in the second in-person workshop, and 8 participated in the in-depth face-to-face interviews. The guidance document was iteratively reviewed by all working group members and the International Advisory Panel. There was substantial variation in: (a) sources and types of RWD being used in HTA, and (b) the relative importance and prioritization of RWE being used for policy-making. A list of national-level databases and other sources of RWD available in each country was compiled. A list of useful guidance on data collection, quality assurance and study design were also compiled. CONCLUSION: The REALISE guidance document serves to align the collection of better quality RWD and generation of reliable RWE to ultimately inform HTA in Asia.

Assessing the cost-effectiveness of mepolizumab as add-on therapy to standard of care for severe eosinophilic asthma in Singapore.

OBJECTIVE: To evaluate the cost-effectiveness of mepolizumab added to standard of care (SOC) compared with SOC alone among patients with severe uncontrolled eosinophilic asthma in the Singapore setting. METHODS: A Markov model with three health states (asthma on mepolizumab and SOC, asthma on SOC alone, and death) was developed from a healthcare system perspective over a lifetime horizon. During each 4-week cycle, patients in the non-death health states could experience asthma exacerbations requiring oral corticosteroid burst, emergency department visit, or hospitalization. Asthma-related mortality following an exacerbation or all-cause mortality could also occur at each cycle. The model was populated using local costs while utilities were derived from international literature. Transition probabilities were obtained from a mixture of Singapore-specific and internationally published data. RESULTS: The base-case analysis comparing mepolizumab plus SOC with SOC alone resulted in an incremental cost-effectiveness ratio (ICER) of SGD335 486 (USD238 195) per quality-adjusted life-year (QALY) gained. Sensitivity analysis demonstrated that the ICER was most sensitive to the price of mepolizumab, followed by the proportion of exacerbations which required hospital intensive care. Despite restricting mepolizumab use to patients with a higher baseline exacerbation rate (3 in the past year) in a scenario analysis, the ICER remained high at SGD238 876 (USD 169 602) per QALY gained. CONCLUSION: At its current price, mepolizumab is not considered a cost-effective use of healthcare resources in Singapore. Substantial price reductions for mepolizumab are required to improve its cost-effectiveness to an acceptable range. These results will be useful to inform national funding decisions.

Cost-effectiveness analysis of the nonavalent human papillomavirus vaccine for the prevention of cervical cancer in Singapore.

BACKGROUND: The nonavalent human papillomavirus (HPV) vaccine has been shown to extend protection against oncogenic HPV types 31/33/45/52/58 (HPV-OV) not covered by the bivalent and quadrivalent HPV vaccines. Besides its clinical benefit, evidence on the economic value of the nonavalent vaccine is required to inform local vaccination strategies and funding decisions. This study evaluated the cost-effectiveness of replacing the bivalent vaccine with the nonavalent vaccine in the national school-based HPV vaccination programme in Singapore. METHODS: An existing age-structured dynamic transmission model coupled with stochastic individual-based simulations was adapted to project the health and economic impact of vaccinating 13-year-old girls with two doses of the nonavalent or bivalent HPV vaccines in Singapore. Direct costs (in Singapore dollars, S$) were obtained from public healthcare institutions in Singapore, while health state utilities were sourced from the literature. Incremental cost-effectiveness ratios (ICERs) were estimated over a lifetime horizon, from a healthcare system perspective. Probabilistic sensitivity analysis was performed to obtain the ICERs and corresponding variations across variable uncertainty. Particularly, this study tested the scenarios of lifelong and 20-year vaccine-induced protection, assumed 96.0% and 22.3% cross-protection against HPV-OV by nonavalent and bivalent vaccines respectively, and fixed vaccine prices per dose at S$188 for nonavalent and S$61.50 for bivalent vaccines. RESULTS: Compared with the bivalent vaccine, the use of the nonavalent vaccine was associated with an ICER of S$61,629 per quality-adjusted life year gained in the base case. The result was robust across a range of plausible input values, and to assumptions regarding the duration of vaccine protection. CONCLUSION: Given the high ICER, the nonavalent vaccine is unlikely to represent a cost-effective option compared with the bivalent vaccine for school-based HPV vaccination of 13-year old female students in Singapore. Substantial price reductions would be required to justify its inclusion in the school-based programme in the future.

A landscape analysis of health technology assessment capacity in the Association of South-East Asian Nations region.

BACKGROUND: Progress towards achieving Universal Health Coverage and institutionalizing healthcare priority setting through health technology assessment (HTA) in the Association of South-East Asian Nations (ASEAN) region varies considerably across countries because of differences in healthcare expenditure, political support, access to health information and technology infrastructure. To explore the status and capacity of HTA in the region, the ASEAN Secretariat requested for member countries to be surveyed to identify existing gaps and to propose solutions to help countries develop and streamline their priority-setting processes for improved healthcare decision-making. METHODS: A mixed survey questionnaire with open- and closed-ended questions relating to HTA governance, HTA infrastructure, supply and demand of HTA and global HTA networking opportunities in each country was administered electronically to representatives of HTA nodal agencies of all ASEAN members. In-person meetings or email correspondence were used to clarify or validate any unclear responses. Results were collated and presented quantitatively. RESULTS: Responses from eight out of ten member countries were analysed. The results illustrate that countries in the ASEAN region are at different stages of HTA institutionalization. While Malaysia, Singapore and Thailand have well-established processes and methods for priority setting through HTA, other countries, such as Cambodia, Indonesia, Lao PDR, Myanmar, the Philippines and Vietnam, have begun to develop HTA systems in their countries by establishing nodal agencies or conducting ad-hoc activities. DISCUSSION AND CONCLUSION: The study provides a general overview of the HTA landscape in ASEAN countries. Systematic efforts to mitigate the gaps between the demand and supply of HTA in each country are required while ensuring adequate participation from stakeholders so that decisions for resource allocation are made in a fair, legitimate and transparent manner and are relevant to each local context.

Cost-effectiveness of pertuzumab and trastuzumab biosimilar combination therapy as initial treatment for HER2-positive metastatic breast cancer in Singapore.

BACKGROUND: This study evaluates the cost-effectiveness of pertuzumab with trastuzumab biosimilar and docetaxel as initial treatment for HER2-positive metastatic breast cancer (MBC) in Singapore. METHODS: A partitioned survival model with three health states was developed to evaluate the cost-effectiveness of trastuzumab biosimilar and docetaxel with or without pertuzumab from a healthcare system perspective over a 15-year time horizon for patients with HER2-positive MBC. Key clinical inputs were derived from the CLEOPATRA trial. Health state utilities were derived from the literature and direct medical costs were obtained from local public healthcare institutions. RESULTS: The base-case resulted in an incremental cost-effectiveness ratio (ICER) of SGD366,658 (USD272,244) per quality-adjusted life-year (QALY) gained. One-way sensitivity analyses showed that the ICER was sensitive to utilities in the progression-free state, price of pertuzumab and time horizon. When the price for trastuzumab reference biologic (branded) was applied, the ICER was even higher (SGD426,996 [USD317,045]/QALY). CONCLUSION: Although trastuzumab biosimilar reduced the cost of the pertuzumab combination regimen, the ICER remained high and was not cost effective in Singapore's context. As pertuzumab contributed 80% of the overall combination treatment cost, price reductions for pertuzumab will be required to improve the cost-effectiveness of combination treatment to an acceptable level.

Cost-effectiveness of olaparib maintenance therapy when used with and without restriction by BRCA1/2 mutation status for platinum-sensitive relapsed ovarian cancer.

Objectives: To determine whether olaparib maintenance therapy, used with and without restriction by BRCA1/2 mutation status, is cost-effective at the population level for platinum-sensitive relapsed ovarian cancer in Singapore.Methods: A partitioned survival model compared three management strategies: 1) treat all patients with olaparib; 2) test for germline BRCA1/2 mutation, followed by targeted olaparib use in mutation carriers only; 3) observe all patients. Mature overall survival (OS) data from Study 19 and a 15-year time horizon were used and direct medical costs were applied. Sensitivity analyses were conducted to explore uncertainties.Results: Treating all patients with olaparib was the most costly and effective strategy, followed by targeted olaparib use, and observation of all patients. Base-case incremental cost-effectiveness ratios (ICERs) for all-olaparib and targeted use strategies were SGD133,394 (USD100,926) and SGD115,736 (USD87,566) per quality-adjusted life year (QALY) gained, respectively, compared to observation. ICERs were most sensitive to the cost of olaparib, time horizon and discount rate for outcomes. When these parameters were varied, ICERs remained above SGD92,000 (USD69,607)/QALY.Conclusions: At the current price, olaparib is not cost-effective when used with or without restriction by BRCA1/2 mutation status in Singapore, despite taking into account potential OS improvement over a long time horizon.

Cost-effectiveness of ribociclib as initial treatment for premenopausal women with advanced breast cancer in Singapore.

BACKGROUND: CDK4/6 inhibitors have shown promising results for treating advanced breast cancer (ABC) and are routinely used in Singapore. In view of their high costs, it is important to assess their relative value compared to existing standards of care in the local setting. AIMS: This study evaluates the cost-effectiveness of adding ribociclib to goserelin and a nonsteroidal aromatase inhibitor or tamoxifen as initial therapy for premenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) ABC in Singapore. METHODS: A partitioned survival model with four health states (progression-free on first-line treatment, progression-free on second-line treatment, progressed disease, and death) was developed from a healthcare system perspective over a 10-year time horizon. Key clinical inputs were derived from the MONALEESA-7 trial, and survival curves were extrapolated beyond the trial period. Health state utilities were derived from the literature and direct medical costs were obtained from local public healthcare institutions. A discount rate of 3% was applied to both costs and outcomes. One-way deterministic and probabilistic sensitivity analyses were conducted to explore uncertainties. RESULTS: The base-case analysis resulted in an incremental cost-effectiveness ratio (ICER) of SGD197, 667 per quality-adjusted life-year. Sensitivity analyses showed that the ICER was sensitive to the survival parametric distribution, ribociclib price, time horizon, and utility weights used. Even when these were varied, ICERs remained high and not cost-effective in the local context. CONCLUSION: At its current price, adding ribociclib to endocrine therapy is unlikely to be cost-effective in Singapore for HR+, HER2- ABC. Results from this study are useful to inform future funding decisions for CDK4/6 inhibitors alongside other factors including clinical effectiveness, safety, and budget impact considerations.

Real-world data for health technology assessment for reimbursement decisions in Asia: current landscape and a way forward.

There is growing interest globally in using real-world data (RWD) and real-world evidence (RWE) for health technology assessment (HTA). Optimal collection, analysis, and use of RWD/RWE to inform HTA requires a conceptual framework to standardize processes and ensure consistency. However, such framework is currently lacking in Asia, a region that is likely to benefit from RWD/RWE for at least two reasons. First, there is often limited Asian representation in clinical trials unless specifically conducted in Asian populations, and RWD may help to fill the evidence gap. Second, in a few Asian health systems, reimbursement decisions are not made at market entry; thus, allowing RWD/RWE to be collected to give more certainty about the effectiveness of technologies in the local setting and inform their appropriate use. Furthermore, an alignment of RWD/RWE policies across Asia would equip decision makers with context-relevant evidence, and improve timely patient access to new technologies. Using data collected from eleven health systems in Asia, this paper provides a review of the current landscape of RWD/RWE in Asia to inform HTA and explores a way forward to align policies within the region. This paper concludes with a proposal to establish an international collaboration among academics and HTA agencies in the region: the REAL World Data In ASia for HEalth Technology Assessment in Reimbursement (REALISE) working group, which seeks to develop a non-binding guidance document on the use of RWD/RWE to inform HTA for decision making in Asia.

Cost-effectiveness analysis of pembrolizumab monotherapy versus chemotherapy for previously untreated advanced non-small cell lung cancer.

Objective: To assess the cost-effectiveness of pembrolizumab monotherapy compared with standard chemotherapy for the treatment of advanced non-small cell lung cancer (NSCLC) in previously untreated adults who have a high programmed death ligand 1 (PD-L1) tumor proportion score of 50% or greater in Singapore.Materials and methods: A partitioned-survival analysis model was developed from a healthcare system's perspective that extrapolated clinical and economic outcomes of first-line pembrolizumab (maximum treatment duration of 2 years) versus platinum doublet chemotherapy over a 10-year time horizon for patients with advanced NSCLC. The model consisted of three health states: alive with no progression, alive with progression, and dead. Key clinical inputs were based on Kaplan-Meier survival curves from the interim (median follow-up = 11.2 months) and updated analysis (median follow-up = 25.2 months) of the KEYNOTE-024 randomized controlled trial. Local cost data were applied. Utilities were derived from published international estimates. Both one-way and multivariate probabilistic sensitivity analyses (PSA) were conducted to identify key drivers of the results.Results: Using the results from the updated analysis of KEYNOTE-024, patients treated with pembrolizumab experienced more quality adjusted life-years (QALYs), but incurred higher costs compared to chemotherapy over a 10-year time horizon (pembrolizumab: 1.9983 QALYs, SGD215,761; chemotherapy: 1.1317 QALYs, SGD70,444). The base-case incremental cost-effectiveness ratio (ICER) was SGD167,692 per QALY gained. One-way sensitivity analysis showed the ICER was most sensitive to the cost of pembrolizumab, followed by the time horizon. Multivariate PSA indicated that pembrolizumab had 0% probability of being cost-effective at a hypothetical willingness-to-pay threshold of SGD100,000 per QALY gained.Conclusion: While pembrolizumab is superior to standard chemotherapy in improving overall survival and progression-free survival, results suggest that it is unlikely to be cost-effective at its current price in Singapore. Factors including clinical effectiveness, safety, and budget impact should also be considered when making national funding decisions.

Cost-effectiveness of sequential urate lowering therapies for the management of gout in Singapore.

Aims: Allopurinol is the most common urate lowering therapy (ULT) used to treat gout but may cause life-threatening severe cutaneous adverse reactions (SCAR) in a small number of patients. Risk of SCAR is increased for patients with the HLA-B*58:01 genotype. When alternative ULT is required, febuxostat or probenecid are recommended. The aim of this study was to conduct a cost-utility analysis of sequential ULT treatment strategies for gout, including strategies with and without HLA-B*58:01 genotyping prior to treatment initiation, with a view to inform optimal gout management in Singapore.Materials and methods: A Markov model was developed from the Singapore healthcare payer perspective. Reflecting local practice, 12 different treatment strategies containing at least one ULT (allopurinol, febuxostat, probenecid) were evaluated in adults with gout. Response rates (SUA < 6mg/dL) were derived from an in-house network meta-analysis and from published literature. Incremental cost-effectiveness ratios (ICERs) were calculated over a 30-year time horizon, with costs and benefits discounted at 3% per annum. Sensitivity analyses were conducted to explore uncertainties.Results: Sequential treatment of allopurinol 300 mg/day-allopurinol 600 mg/day-probenecid ("standard of care") was cost-effective compared to no ULT, with an ICER of SGD1,584/QALY. Allopurinol300-allopurinol600-probenecid-febuxostat sequence compared to allopurinol300-allopurinol600-probenecid had an ICER of SGD11,400/QALY. All other treatment strategies were dominated by preceding strategies. Treatment strategies incorporating HLA-B*58:01 genotyping before ULT use were dominated by the corresponding non-genotyping strategy.Conclusions: Current standard of care (allopurinol300-allopurinol 600-probenecid) for gout is cost-effective compared with no ULT in the local context. Febuxostat is unlikely to be cost-effective in Singapore at current prices unless it is used last-line.

Landscape analysis of health technology assessment (HTA): systems and practices in Asia.

This paper explores the characteristics of health technology assessment (HTA) systems and practices in Asia. Representatives from nine countries were surveyed to understand each step of the HTA pathway. The analysis finds that although there are similarities in the processes of HTA and its application to inform decision making, there is variation in the number of topics assessed and the stakeholders involved in each step of the process. There is limited availability of resources and technical capacity and countries adopt different means to overcome these challenges by accepting industry submissions or adapting findings from other regions. Inclusion of stakeholders in the process of selecting topics, generating evidence, and making funding recommendations is critical to ensure relevance of HTA to country priorities. Lessons from this analysis may be instructive to other countries implementing HTA processes and inform future research on the feasibility of implementing a harmonized HTA system in the region.

Cost-Effectiveness Analysis of Sunitinib versus Interferon-Alfa for First-Line Treatment of Advanced and/or Metastatic Renal Cell Carcinoma in Singapore.

OBJECTIVES: This study was conducted to evaluate the cost-effectiveness of sunitinib versus interferon-alfa for the treatment of advanced and/or metastatic renal cell carcinoma (RCC) in Singapore. METHODS: A partitioned survival model with three health states (progression-free, progressive disease, and death) was developed from a healthcare payer perspective over a 10-year time horizon. Survival curves from the pivotal trial of sunitinib versus interferon-alfa were extrapolated beyond the trial period to estimate the underlying progression-free survival and overall survival parametric distributions. Health state utilities were derived from the literature and direct costs were sourced from local public healthcare institutions. The sunitinib dose in the model reflected local prescribing practices whereby a combination of 50 mg (28 percent) and 37.5 mg (72 percent) strengths are used. RESULTS: The base-case analysis comparing sunitinib versus interferon-alfa resulted in an incremental cost effectiveness ratio (ICER) of SGD191,061 (USD139,757) per quality-adjusted life-year gained. Sensitivity analysis demonstrated that the ICER was most sensitive to variations in the utility value assumed for the progression-free health state and the price of sunitinib. CONCLUSIONS: In the absence of any price reduction, sunitinib had an exceedingly high ICER and was not considered a cost-effective use of healthcare resources in Singapore's context for the first-line treatment of advanced RCC. The findings from our evaluation will be useful to inform local healthcare decision making and resource allocations for tyrosine kinase inhibitors when appraised alongside comparative clinical effectiveness data and payer affordability considerations.

Health Technology Assessment and Its Use in Drug Policies: Singapore.

INTRODUCTION: Singapore has a robust health care system that is well known for delivering good health outcomes. In the public health care sector, subsidies and financial assistance are provided for drugs listed on the Standard Drug List and Medication Assistance Fund. Additional financing mechanisms are also available to provide further support for patients in need. With new technologies entering the market at high costs, health technology assessment (HTA) is playing an increasingly important role to inform their relative value and determine how best to allocate finite health care resources to ensure long-term sustainability of the health care system. ROLE OF HTA: National HTA efforts are currently focused on informing subsidy decision making and improving patient access to cost-effective drugs. The Agency for Care Effectiveness (ACE) was established in 2015 to support the Ministry of Health Drug Advisory Committee make evidence-based recommendations for the public funding of drugs. Standardized HTA methods and processes have been developed in line with international best practice to ensure that ACE's evaluations are conducted in a consistent and robust manner. Since ACE's establishment, subsidies are now provided earlier within a drug's life cycle, and value-based pricing has led to more cost-effective prices being negotiated with companies to improve affordability for patients and the public health care system. CONCLUSION: To achieve greater impact, Singapore needs to expand its HTA capacity beyond subsidy decision making and drive appropriate care in a sustainable manner for future generations.

Cost effectiveness analysis of afatinib versus pemetrexed-cisplatin for first-line treatment of locally advanced or metastatic EGFR mutation positive non-small-cell lung cancer from the Singapore healthcare payer's perspective.

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.