Patient Involvement in the Health Technology Assessment Process in Taiwan.

The COVID-19 pandemic initially had a smaller impact on Taiwan than on most other industrialized countries. However, an outbreak in late April 2021 led to a sharp surge in cases from mid-May 2021. Patient involvement in the health technology assessment (HTA) process, however, was not much affected by this; virtual meetings were implemented. This descriptive paper presents an overview of patient involvement in the HTA process in Taiwan via the National Health Insurance Administration (NHIA) online submission platform, participation in appraisal committees, education programs, and cooperation with patients' organizations, and outlines its progress and challenges. The National Health Insurance Act, amended in 2013, protects patients' rights and invites them to voice their opinions, which are then presented to the relevant authority. Based on this act, various mechanisms have been developed to involve patients, caregivers, and patient organizations in both the HTA and the reimbursement process. Prior to the Pharmaceutical Benefit and Reimbursement Scheme (PBRS) Joint Committee meeting, the NHIA built an online platform that allows patients to submit their opinions, which are then incorporated into the HTA reports. The results are also discussed with patient representatives, following which the related documents are published on the NHIA website. From May 2015 to December 2020, 30 patients' insights were published before the PBRS Joint Committee meetings. Of these, 19 (63%) were related to oncology cases. In Taiwan, approaches to fostering patient engagement include the use of a platform for patients' and patients groups' input, among others. Although patient engagement is important for understanding the needs of the target patient population, challenges in ensuring timely patient engagement and provision of relevant resources remain. In addition, further efforts are needed to implement and improve the visibility of patient input in the HTA process.

Lessons learned from the reimbursement policy for immune checkpoint inhibitors and real-world data collection in Taiwan.

This paper describes the reimbursement policy for immune checkpoint inhibitors in Taiwan and provides a perspective to improve the quality, consistency, and transparency of decision making. Global trends for cancer treatment have shifted from chemotherapies to targeted therapies and immuno-oncology (IO) medicine, leading to significant increases in treatment costs. To enhance the accessibility of advanced therapy, the Taiwan National Health Insurance Administration announced two pathways for high-cost medicine: the managed entry agreement and a set of general rules of reimbursement submission for high-cost drugs. To further manage the financial burden on Taiwan's national health insurance system, the policy makers introduced novel inhibitory drugs for cancer immune checkpoints, subject to a maximum annual budget of NT$800 million (≈US$26.7 million). In April 2019, a national registry was established for patients undergoing cancer immunotherapy. Clinical characteristics, treatment duration, toxicity, and the outcome of the postcheckpoint inhibitor treatments were recorded. By analyzing real-world data, we assess the therapeutic effect of IO treatment in Taiwanese patients, thereby enabling payers to adjust payment regulations and rules for reimbursement. The Health Technology Assessment Team plays an important role in drawing upon the evidence to support policy making. Under an implemented cost-management mechanism, Taiwan's high-cost drug policy has enabled patients to access new medicines and maximized patient benefits.

Outcomes and Impacts of 10-Year HTA Implementation in Taiwan.

OBJECTIVES: In 2007, Taiwan began conducting health technology assessments (HTA) to support the National Health Insurance Administration (NHIA) in its reimbursement decisions for drugs, medical devices, and medical services. METHODS: In this study, the development, missions, and procedures of the implementation of HTA in Taiwan are briefly introduced. Moreover, the value of HTA is examined by reviewing the outcomes and impacts of recent HTA-related research projects, which are classified into five categories: (i) pharmaceutical products, (ii) medical procedures, (iii) medical devices, (iv) health policy, and (v) social care. RESULTS: Overall, the 10-year implementation of HTA has not only supported the government's decision making but also enhanced patient care. Furthermore, patient evidence has been highlighted, and patient care pathways have been transformed through patient involvement in HTA. CONCLUSIONS: In conclusion, HTA's value has been determined by both government and social aspects in Taiwan.

Valuation of the EQ-5D-5L in Taiwan.

OBJECTIVES: To date, a value set for the EQ-5D-5L based on the health state preferences of the general Taiwanese population has not been available. This study aimed to develop a Taiwanese value set for EQ-5D-5L to facilitate health technology assessment for medical products and services. METHODS: An international standardized protocol for EQ-5D-5L valuation studies developed by the EuroQol group was adopted. Adult members of the general public were recruited from six geographic regions in Taiwan. In computer-based face-to-face interviews, each participant completed 10 composite time trade-off (C-TTO) tasks and 7 discrete choice experiment (DCE) tasks. The C-TTO and DCE data were modeled alone or in combination (using hybrid models) with additive models containing 20 dummy variables as main effects. The model performance was assessed both quantitatively and qualitatively (mainly logical consistency and prediction patterns). RESULTS: Of 1,073 recruited participants, 1,000 completed the study. Approximately 13% of observed utility values were -1 in the C-TTO tasks. The hybrid model, using all available data that assumed C-TTO response values left-censored at -1 and with main effects coefficients with logical consistency (monotonicity), was considered as the most appropriate model. The predicted utility ranged from -1.0259 to 1. CONCLUSIONS: An EQ-5D-5L value set was developed for Taiwan using an established study protocol and a representative sample of the general population. This may facilitate health economic evaluations and decision making on resource allocation under Taiwan's national health insurance program in the future.

Stem cell therapy on skin: Mechanisms, recent advances and drug reviewing issues.

Stem cell products and its clinical applications have been widely discussed in recent years, particularly when the Japanese "induced pluripotent stem cells" founder Dr. Yamanaka was awarded as Nobel Prize laureate in 2013. For decades, major progresses have been achieved in the stem cell biology field, and more and more evidence showed that skin stem cells are involved in the process of skin repair. Stem/progenitor cells of the epidermis are recognized to play the most essential role in the tissue regeneration of skin. In this review, we first illustrated basic stem cell characteristics and various stem cell subtypes resided in the skin. Second, we provided several literatures to elucidate how stem/progenitor cells collaborate in the process of skin repair with the evidence from animal model studies and in vitro experiments. Third, we also introduced several examples of skin cell products on the pharmaceutic market and the ongoing clinical trials aiming for unmet medical difficulties of skin. Last but not least, we summarized general reviewing concerns and some disputatious issues on dermatological cell products. With this concise review, we hope to provide further beneficial suggestions for the development of more effective and safer dermatological stem/progenitor cell products in the future.

Epidemiology, clinical profile and treatment patterns of venous thromboembolism in cancer patients in Taiwan: a population-based study.

BACKGROUND: Venous thromboembolism (VTE) is a clinically significant complication that is well documented among Caucasian cancer patients. However, evidence regarding VTE incidence and treatment among Asian cancer patients is very limited. The objective of this study is to investigate the incidence, risk factors and management of VTE among Taiwanese cancer patients. METHODS: Using Taiwan's National Health Insurance Research Database, we identified 43,855 newly diagnosed cancer patients between 2001 and 2008. Two alternative algorithms for identifying VTE event were explored to better quantify a range of incidence rates of VTE in our cancer patients. Multivariable logistic regression models were used to explore VTE risk factors. RESULTS: The incidence rates of VTE were 9.9 (algorithm 1) and 3.4 (algorithm 2) per 1,000 person-years, respectively. The incidence rates were higher in certain cancers, particularly liver, pancreas, and lung. Significant risk factors for VTE were site of cancer, prior history of VTE, chemotherapy and major surgeries. Long-term anticoagulant therapy was initiated in 64.1% patients with VTE and 72.2% of them received warfarin alone. Approximately two-thirds of patients with VTE received ≤ 3 months of anticoagulant therapy. CONCLUSION: Incidence of cancer-related VTE is lower among Taiwanese compared to Caucasian populations. Nevertheless, risk factors for cancer-related VTE found in our study were consistent with current literature.

Suboptimal duration of granulocyte colony-stimulating factor use and chemotherapy-induced neutropenia in women diagnosed with breast cancer.

PURPOSE: Prophylactic use of granulocyte colony-stimulating factor (G-CSF) is recommended for cancer patients who are at high risk of neutropenic events. However, whether the clinical effectiveness of G-CSF from randomized controlled trials translates into "real-world" clinical practice is questionable. The goal of this retrospective cohort study was to examine the impact of G-CSF prophylaxis and other potential risk factors of severe neutropenia in women with breast cancer. METHODS: Our study subjects were women who were diagnosed with breast cancer and who received a new course of chemotherapy between January 1, 2010, and December 31, 2010, at a cancer center in Taiwan. Generalized estimating equations were applied to examine the association between G-CSF prophylaxis and neutropenic events. FINDINGS: We identified 353 women with breast cancer who received a total of 2776 cycles of chemotherapy. G-CSF was used as primary prophylaxis in 7% (n = 202) of cycles and as secondary prophylaxis in 11% (n = 319) of cycles. The mean duration of G-CSF for primary and secondary prophylaxis was 4.9 and 3.7 days, respectively. A chemotherapy regimen with high risk of febrile neutropenia was found to be a risk factor for severe neutropenic events (odds ratio, 3.22 [95% CI, 1.97-5.27]). Prophylactic use of G-CSF was not statistically significantly associated with febrile neutropenia. IMPLICATIONS: The major determinants of neutropenic events among patients with breast cancer were the content and intensity of chemotherapy regimens. Suboptimal use of G-CSF may not be effective in preventing neutropenic events among women with breast cancer.

Risk of bladder cancer in diabetic patients treated with rosiglitazone or pioglitazone: a nested case­control study.

BACKGROUND: Evidence has emerged that pioglitazone may increase the risk of bladder cancer, but the association has not been confirmed. This potential risk also has not been evaluated in users of rosiglitazone. OBJECTIVE: Using Taiwan's National Health Insurance Research Database (NHIRD), this large population-based nested case­control study was conducted to explore the relationship between the use of rosiglitazone or pioglitazone and risk of bladder cancer in diabetic patients. METHODS: We identified 3,412 cases of newly diagnosed bladder cancer and 17,060 controls (1:5 matched by age and sex) among a diabetic patient cohort from the NHIRD.We defined an index date for each case as the date of first hospitalization for bladder cancer. Each control was assigned the index date of their corresponding case. Multivariable conditional logistic regressions were used to estimate the association between exposure (timing and duration) to rosiglitazone or pioglitazone and bladder cancer. We defined rosiglitazone or pioglitazone exposure as ''current'' if the prescription duration covered the index date or ended at 90 days before, as ''recent'' if it ended 91­180 days before the index date, or as ''past'' if the last prescription ended more than 180 days before. Duration of rosiglitazone or pioglitazone use was defined based on the cumulative days of exposure prior to the index date: < 1, 1­2 and ≥ 2 years. RESULTS: Rosiglitazone and pioglitazone use were associated with risk of bladder cancer and the associations were stronger with a longer term of exposure (pioglitazone < 1 year odds ratio [OR] 1.45 [95 % CI 1.12­1.87, p < 0.01], 1­2 years OR 1.74 [95 % CI 1.05­2.90, p = 0.03] and ≥ 2 years OR 2.93 [95 % CI 1.59­5.38, p < 0.01]; rosiglitazone < 1 year OR 0.98 [95 % CI0.82­1.17, p = 0.81], 1­2 years OR 1.78 [95 % CI 1.31­2.39, < 0.01] and ≥ 2 years OR 2.00 [95 % CI 1.37­2.92, p < 0.01]). CONCLUSIONS: Long-term exposures to pioglitazone and rosiglitazone were associated with higher odds of bladder cancer, and the highest odds were seen in users with ≥ 2 years of exposure.

Age, dementia and care patterns after admission for acute coronary syndrome: an analysis from a nationwide cohort under the National Health Insurance coverage.

BACKGROUND: The number of elderly and the prevalence of dementia have grown considerably in recent years. Little is known about how aging and dementia affect care patterns after discharge for acute coronary syndrome (ACS). OBJECTIVE: This study was designed to assess the impact of dementia on care patterns after admission for patients with ACS across different age groups. METHODS: Of 87,321 patients hospitalized for ACS between 1 January 2006 and 31 December 2007, 1,835 patients with dementia and 3,670 matched patients without dementia (1:2 ratio, matched by age, sex and hospital level) were identified from Taiwan's National Health Insurance Research Database. Use of interventional therapies at hospitalization and guideline-recommended medications post-discharge were compared between patients with and without dementia across different age groups (≤65, 66-75, 76-85, ≥86 years). Multivariate logistic regression models were performed to examine the impact of dementia on care patterns. RESULTS: Overall, dementia was associated with a 27% lower likelihood of receipt of interventional therapies [adjusted odds ratio (OR) = 0.73; 95% CI 0.63, 0.83] and a 22% lower likelihood of guideline-recommended medications (adjusted OR = 0.78; 95% CI 0.68, 0.89) in ACS patients. The use of interventional therapies and guideline-recommended medications decreased with age, and interactions between age and dementia were found. The proportions of patients receiving interventional therapies were 39.4% (without dementia) versus 21.8% (with dementia) in the youngest age group and 18.6% (without dementia) versus 14.5% (with dementia) in the oldest age group. Patients with dementia (age ≤65 years 73.6%; age 66-75 years 82.3%; age 76-85 years 71.8%; age ≥86 years 55.6%) were less likely to receive guideline-recommended medications as compared with those without dementia (age ≤65 years 85.6%; age 66-75 years 87.5%; age 76-85 years 81.2%; age ≥86 years 62.0%). CONCLUSION: Dementia and aging were associated with decreased use of interventional therapies and guideline-recommended medications in ACS patients.

Cardiovascular outcomes associated with concomitant use of clopidogrel and proton pump inhibitors in patients with acute coronary syndrome in Taiwan.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Conflicting results have been reported regarding the increased risk of adverse outcomes in the concomitant use of clopidogrel and proton pump inhibitors (PPIs) compared with the use of clopidogrel alone. WHAT THIS STUDY ADDS: Our study indicated no statistically significant increase in the risk of rehospitalization for acute coronary syndrome due to concurrent use of clopidogrel and PPIs in an Asian population with higher prevalence of CYP2C19 intermediate and poor metabolizers. Among all PPIs, only omeprazole was found to be statistically significantly associated with an increased risk of rehospitalization for acute coronary syndrome. AIMS Our study aimed to examine the impact of concomitant use of proton pump inhibitors (PPIs) with clopidogrel on the cardiovascular outcomes of patients with acute coronary syndrome (ACS). Furthermore, we sought to quantify the effects of five individual PPIs when used concomitantly with clopidogrel. METHODS: We conducted a retrospective cohort study of patients who were newly hospitalized for ACS between 1 January 2006 and 31 December 2007 retrieved from the Taiwan National Health Insurance Research Database (NHIRD) and who were prescribed clopidogrel (n= 37 099) during the follow-up period. A propensity score technique was used to establish a matched cohort in 1:1 ratio (n= 5173 for each group). The primary clinical outcome was rehospitalization for ACS, while secondary outcomes were rehospitalization for percutaneous transluminal coronary angioplasty (PTCA) with stent, PTCA without stent and revascularization (PTCA or coronary artery bypass graft surgery) after the discharge date for the index ACS event. RESULTS: The adjusted hazard ratio of rehospitalization for ACS was 1.052 (95% confidence interval, 0.971-1.139; P= 0.214) in the propensity score matched cohort. Among all PPIs, only omeprazole was found to be statistically significantly associated with an increased risk of rehospitalization for ACS (adjusted hazard ratio, 1.226; 95% confidence interval, 1.066-1.410; P= 0.004). Concomitant use of esomeprazole, pantoprazole, rabeprazole and lansoprazole did not increase the risk. CONCLUSIONS: Our study indicated no statistically significant increase in the risk of rehospitalization for ACS due to concurrent use of clopidogrel and PPIs overall. Among individual PPIs, only omeprazole was found to be statistically significantly associated with increased risk of rehospitalization for ACS.

Association between mood stabilizers and hypothyroidism in patients with bipolar disorders: a nested, matched case-control study.

OBJECTIVES: This study investigated whether lithium, carbamazepine, and valproate increased the risk for hypothyroidism using Taiwan's National Health Insurance Dataset. METHODS: The sample included 557 bipolar disorder patients with incident hypothyroidism first diagnosed between 1998 and 2004, and 2,228 sex-, age-, and index date-matched bipolar disorder patients without hypothyroidism from 1996-2004. We compared the use of lithium, carbamazepine, and valproate before the onset of hypothyroidism between the two groups using a conditional logistical regression model. RESULTS: Compared with patients who had never used any of the three mood stabilizers, patients were more likely to have hypothyroidism if they only used carbamazepine [odds ratio (OR) = 1.68; 95% confidence interval (CI): 1.07-2.65]; or comedication of lithium and valproate (OR = 2.40; 95% CI: 1.70-3.40), lithium and carbamazepine (OR = 1.52; 95% CI: 1.10-2.08), and three mood stabilizers (OR = 2.34; 95% CI: 1.68-3.25). There was a dose-response relationship between the number of mood stabilizers and risk for hypothyroidism (OR = 1.34, 95% CI: 1.21-1.49) and a significant interaction between lithium and valproate on the risk for hypothyroidism (p = 0.020). CONCLUSIONS: Our findings indicate that lithium, carbamazepine, and valproate may increase the risk for hypothyroidism, particularly if combined, and suggest regular monitoring of thyroid function and monotherapy of mood stabilizers for treating patients with bipolar disorders.

The influence of estimated creatinine clearance on plasma homocysteine in hypertensive patients with normal serum creatinine.

OBJECTIVES: To examine the relation of estimated creatinine clearance (eCrCl) and plasma total homocysteine (tHcy) in hypertensive patients with a normal serum creatinine level. DESIGN AND METHODS: A total of 137 hypertensive patients (mean age 66.6 years, 69 men) with serum creatinine level 60 mL/min/1.73 m(2)). The CRI group was older (p<0.001), had higher tHcy (p<0.001), higher serum urea nitrogen (p<0.001), higher serum creatinine (p<0.001), lower eCrCl (p<0.001), and lower diastolic blood pressure (p=0.001). In univariate analysis, eCrCl had the strongest correlation with tHcy (r=-0.453, p<0.001). Significant correlations, ranging in decreasing order from r=-0.418, p<0.001 to r=-0.170, p=0.047, were also noted between tHcy and twelve other variables. In multivariate analysis, only eCrCl (p<0.001), usage of fibrate (p<0.001), serum level of vitamin B(12) (p=0.002), serum level of folic acid (p=0.009), and smoking (p=0.027) were independent predictors of tHcy. CONCLUSION: eCrCl is a strong independent predictor of tHcy in hypertensive patients with normal serum creatinine.

Usage of the claim database of national health insurance programme for analysis of cisapride-erythromycin co-medication in Taiwan.

PURPOSE: This study aimed to use the National Health Insurance Research Database, Taiwan for risk analysis of concomitant use of cisapride and erythromycin. METHODS: The sample consisted of subjects identified in the Outpatient Sampling Database (OSD) and Longitudinal Health Insurance Database 2000 (LHID 2000), derived from the original claim data of the National Health Insurance Research Database, Taiwan. RESULTS: According to the LHID 2000, a total of 464 individuals experienced 685 episodes of cisapride-erythromycin co-medication prescribed by 295 physicians, revealing a prevalence of 4.5% concomitant use, with higher prevalence in clinics (9.2%) than in other medical institutes (3.7-5.4%). Among the co-medication episodes, 81.9% and 61.2% were prescribed from the same health institutes and by the same physicians, respectively. No medical record of cardiac arrhythmias was found among these patients in 2001 and 2002, probably due to the fact that 78.9% of the 464 individuals were under age 16, 84.0% had short exposure duration (1-4 days) and 98.0% of the episodes were prescribed with a cisapride dose of less than 0.8 mg/kg/day. CONCLUSIONS: Findings from this study suggest that there exists an urgent need for accreditation in terms of pharmacovigilance of clinical sites and their practicing physicians for the prevention of irrational concomitant prescription in Taiwan. Our findings also indicate that it is necessary to investigate other possible conditions of potentially dangerous co-medication in Taiwan and other developing countries.