Introduction
Oncology treatments have shifted from chemotherapy to targeted therapies and, more recently, to immuno-oncology (IO). Novel IO drugs such as ipilimumab, pembrolizumab, nivolumab, and atezolizumab inhibit tumor-induced immune suppression and enable the immune system to fight cancer (Reference Shergold, Millar and Nibbs1;Reference Nishijima, Shachar, Nyrop and Muss2). These medical advancements, coupled with the growing prevalence of cancer, have led to costs spiraling out of control (Reference Dranitsaris, Zhu, Adunlin and Vincent3). In many countries, including Taiwan, as IO therapy becomes the new standard of care in various tumor treatments, the extraordinarily high costs of these IO drugs have resulted in a tremendous challenge for both public and private healthcare systems (Reference Dranitsaris, Zhu, Adunlin and Vincent3).
In Taiwan, cancer is a leading cause of death (4). In 2018, approximately 206.9 out of every 100,000 Taiwanese died from malignant neoplasms, compared with 91.5 out of every 100,000 Taiwanese who died from heart disease (4). According to the National Health Insurance Administration (NHIA), approximately 720,000 patients sought medical treatment for cancer in 2018, indicating an annual increase of 4.14 percent (5). Meanwhile, the total expenses for cancer treatment, including the cost of drugs, examinations, tests, and in-patient care, reached NT$104.5 billion (≈US$3.5 billion), indicating an annual increase of 7.47 percent (5).
Since its implementation in 1995, Taiwan's National Health Insurance (NHI) program has successfully offered universal health coverage to all citizens at affordable costs (Reference Wu, Majeed and Kuo6). Taiwan's NHI is characterized by mandatory enrollment for all citizens, a single-payer government-run insurer, and comprehensive benefits coverage. As of 2014, more than 99 percent of Taiwan's population had enrolled, and this high coverage level has been maintained since then (Reference Wu, Majeed and Kuo6).
The NHI plays a crucial role in safeguarding the nation's health. Although the listing and reimbursing of IO drugs is critical for cancer patient treatments, the drastic increase in cancer prevalence and novel cancer immunotherapy drugs has significantly increased the NHI's financial burden (5). According to IQVIA's 2019 global oncology report, the total cost of oncology drugs in the United States increased from US$29.4 billion to US$56.7 billion between 2013 and 2018 (7). Meanwhile, in Taiwan, the total cost of oncology drugs increased from NT$29 billion (≈US$0.9 billion) to NT$40 billion (≈US$1.3 billion) between 2014 and 2018 (5;8).
New drugs for cancer immunotherapy are costly; for example, classical Hodgkin's lymphoma treatment costs approximately NT$2 million (≈US$66,801) per person (9). This new class of drugs for cancer immune checkpoints also has a wide range of indications. Consequently, the number of potential patients under the indications has increased. If complete coverage were granted, the cost would be nearly NT$6 billion (≈US$198 million), which would push other essential items out of the NHI budget (9).
High-Cost Medicine Policy in Taiwan
In order to enhance the accessibility to advanced therapy, Taiwan's NHIA announced two pathways for high-cost medicines: a managed entry agreement (MEA) and a set of general rules for reimbursement submission for high-cost drugs (10).
Taiwan started conducting a Health Technology Assessment (HTA) in 2007 to support the NHIA in its reimbursement selection, focusing mainly on introducing new drugs into the NHI system, and has continued it ever since. The Division of HTA in the Center of Drug Evaluation, Taiwan (CDE/HTA), was authorized by the Ministry of Health and Welfare (MOHW) to support the HTA program (Reference Kao, Huang, Wu and Gau11). As per the NHIA's request, the CDE/HTA reviewed the MEA programs of other countries in 2017 and also, between 2015 and 2017, conducted clinical and economic assessments of four IO immune checkpoint inhibitors to facilitate policy making (10). In 2017, the International Network of Agencies for HTA (12) revealed that pembrolizumab, nivolumab, and ipilimumab were reimbursed for malignant melanoma or nonsmall cell lung carcinoma in the UK, Canada, Germany, Austria, Spain, and Australia (12). There are various mechanisms in place to share the treatment costs and risks of treatment failure as well as reduce the overall impact of these high-cost drugs on healthcare expenditures (12). The MEA program is one of the most popular mechanisms (Reference Hasan, Lu, Babar and Babar13). Consequently, in September 2018, the MOHW announced the addition of relevant regulations to the MEA (14). Under the authorization of the regulations, the NHIA applied multiple negotiation mechanisms for reaching consensus with marketing authorization holders (14) to accelerate the introduction of good new medicines so that patients can get more timely treatment and care.
After a series of stakeholder meetings and communications in 2018, the NHIA proposed a set of general rules of reimbursement submission for high-cost drugs. The key principles are as follows (10):
(1) High-cost drugs are defined as drugs with expenditures exceeding NT$500 million (≈US$16.6 million) per annum.
(2) Objective, clear, and measurable efficacy end points and evaluation methods must be provided.
(3) A list of side effects and the estimated costs of managing them must be provided.
(4) An approved indication that has been reimbursed in a reference country (Canada, Australia, or the UK) must be included.
(5) An MEA model and related regulations must be proposed.
(6) A Taiwanese pharmaco-economic analysis to support the cost-effectiveness must be provided along with a financial analysis report.
In 2017, the CDE/HTA conducted a review of IO drugs’ safety using model simulations and estimated the eligible user population and costs. The results of the research were adopted and referenced by the NHIA and Pharmaceutical Benefits and Reimbursement Scheme (PBRS) (9). As indicated in the assessment by the CDE/HTA and documentation submitted by the manufacturers, new drugs for cancer immunotherapy are costly at approximately NT$2 to $4 million (≈US$67,000 to $134,000) per person per year (9;15). In addition, the new cancer immune checkpoint drugs have a very wide range of indications, leading to an increase in the number of potential users. As already mentioned, complete coverage could push other items out of the NHI budget (9;15). Thus, to manage the impact on NHI finances of new drugs for cancer immunotherapy, the PBRS Committee held many meetings and ultimately reached a consensus with high-level NHIA officers that new inhibitory drugs for cancer immune checkpoints would be added to NHI coverage with an upper limit of NT$800 million (≈US$26.7 million) in the year 2019 (9;15). The outcomes of using the new immunotherapy drugs have varied widely depending on the type of cancer (9). Based on a drug fee estimate of NT$1 million per person per year, the NT$800 million (≈US$26.7 million) budget for 2019 could support roughly 800 cancer patients (15). The cost of treatment per person for every 4 weeks is estimated to be around NT$176,600 (≈US$5,886). If any of the budget remains due to patients not completing their treatment for any reason, then additional patients could be added (15).
Coverage and reimbursement decisions for expensive medicines should be based on scientific evidence, especially value-based pharmaco-economic evaluations and engaging stakeholders in the process, to account for patient and public preferences (Reference Hasan, Lu, Babar and Babar13). The NHIA also set up a patient registry system to collect real-world data (RWD) from patients using the cancer immune checkpoints (15). The CDE/HTA assessed the RWD to inform decision making at different levels of the healthcare system, and the NHIA thereafter published an executive summary on its Web site (15). On 1 April 2019, the NHIA covered three IO drugs—atezolizumab, pembrolizumab, and nivolumab—for eight diseases and the following ten indications (16):
(1) Unresectable or metastasized melanoma stage 3 or 4;
(2) Second-line drug for advanced squamous cells of nonsmall cell lung cancer;
(3) Third-line drug for advanced nonsmall cell lung cancer;
(4) First-line drug for metastasized nonsmall cell lung cancer;
(5) Classical Hodgkin's lymphoma;
(6) Failed platinum-based chemotherapy and local advanced unresectable or metastasized urothelial carcinoma with disease progression;
(7) Metastasized urothelial carcinoma that cannot be treated with chemotherapy;
(8) Metastasized gastric adenocarcinoma for which second-line or advanced chemotherapy has failed;
(9) Recurrent or metastasized head and neck squamous cell carcinoma;
(10) Advanced or metastatic hepatocellular carcinoma.
Additional novel immunotherapy drugs for cancer that become covered by the NHI or any changes in the requirements will be announced by NHIA (16).
As indicated by the results of some clinical trials, considerable uncertainty remains regarding the effectiveness and safety of these new IO drugs, and the cost-effectiveness is still unclear. Moreover, some of the trials specified a maximum treatment duration of 24 months (16). Thus, to provide all eligible patients a fair treatment opportunity, the maximum coverage period is determined to be 52 weeks (16). Patients using immune checkpoint inhibitors must be evaluated every 12 weeks. Those exhibiting a complete or partial response to the therapy may continue using the drugs, whereas those presenting progressive disease or exhibiting moderate, severe, or life-threatening adverse reactions should immediately cease using the IO (16). Finally, considering the common side effects of new drugs in cancer immunotherapy, only patients with normally acceptable cardiopulmonary, liver, and kidney functionality may use them (16).
Taiwan implemented a precertification mechanism for reimbursing these new immunotherapy drugs, and physicians must upload the following patient information to the precertification page on the NHI virtual private network (16):
(1) Physical status and the results of cardiopulmonary, liver, and kidney function tests;
(2) Programmed death-ligand 1 (PD-L1) expression reports signed by pathologists;
(3) Treatment protocol, including out-of-pocket expenses for chemotherapies or targeted therapies;
(4) Related medical records and images, as well as other necessary documents.
To increase the effectiveness of new drugs, the PBRS decided that coverage priority should be given to patients with high levels of PD-L1 expression because some pivotal trials have shown that such patients are more likely to present improved drug responses (16). For instance, to prescribe pembrolizumab as a second-line drug for nonsmall cell lung cancer, a test report must be attached with Dako 22C3 or Ventana SP263 as the testing instrument showing a PD-L1 expression level of ≥50 percent. For nivolumab to be prescribed as a second-line drug for nonsmall cell lung cancer, a test report must be attached with Dako 28-8 as the testing instrument and a PD-L1 expression level of ≥50 percent. To prescribe atezolizumab as a second-line drug for nonsmall cell lung cancer, a test report must be attached with Ventana SP142 as the testing instrument and a PD-L1 expression level of ≥50 percent on tumor cells or ≥10 percent on tumor-infiltrating cells. All test reports must be signed by a pathologist (16).
In addition, all of the aforementioned regulations reimbursing immune checkpoint inhibitors should be reviewed every 3 months, according to the RWD collected through the precertification mechanism. As of March 2020, a total of 1,490 patients had been accepted for IO treatment and included in the register database (17). Among the 1,154 analyzable cases, approximately 21.1 percent (243/1,154) had a complete or partial response (17). Adverse events were reported and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE). Among 849 analyzable cases, approximately 9.4 percent (80/849) reported immune-related adverse events and 3.9 percent (33/849) discontinued treatment because of side-effects (as of March 2020) (15). For stakeholders’ reference, the NHIA publishes all information in Mandarin (17).
To effectively use the healthcare resources, the reimbursement policy for IO drugs was updated in March 2020. Initially, three IO drugs reimbursed by the NHIA—atezolizumab, pembrolizumab, and nivolumab—received extended coverage from 1 to 2 years, excluding advanced or metastatic hepatocellular carcinoma and metastasized gastric adenocarcinoma because of lower rates of effectiveness with those cancers in Taiwan (16).
Discussion
Over the last 5 years, the introduction of a new class of drugs (IO drugs) has dramatically changed the treatment of various cancers, including lung cancer (Reference Pasello, Pavan, Attili, Bortolami, Bonanno and Menis18). However, despite the increases in overall survival rates seen in some clinical trials, the majority of patients have shown primary resistance and have not benefitted from these agents (Reference Oliva, Spreafico, Taberna, Alemany, Coburn and Mesia19), especially considering the potentially severe immune-related toxicities and their high costs (Reference Oliva, Spreafico, Taberna, Alemany, Coburn and Mesia19). Taiwan is not alone in facing challenges related to rationing and prioritizing access to high-cost medicines; such issues present challenges for all countries. Since 2015, the CDE/HTA team has conducted systematic reviews, as well as clinical and economic assessments, of four IO drugs in the class of immune checkpoint inhibitors to provide evidence for policy-making decisions. However, the outcomes and financial impacts of high-cost medicines remain uncertain. Some countries have implemented MEAs to share the cost of uncertainty between the payer and the marketing authorization holder, thereby facilitating access to new high-cost medicines (Reference Jommi and Babar20). Other countries allow payers to set up special access schemes by allocating funds for nonpublicly reimbursed high-cost medicines (Reference Aggarwal, Fojo, Chamberlain, Davis and Sullivan21), such as the Cancer Drugs Fund established in England in 2010 (Reference Aggarwal, Fojo, Chamberlain, Davis and Sullivan21). A newer approach involves the collection of additional data during a managed access period when patients can access the treatment (Reference Ferrario and Kanavos22). These additional data help policy makers decide whether new treatments should be routinely funded (Reference Ferrario and Kanavos22).
In June 2018, Taiwan established a new policy for submitting novel oncology drugs for consideration of NHI coverage. These general rules of reimbursement of submission for high-cost drugs cover cancer drugs with annual expenditures exceeding NT$500 million (≈US$16.6 million), although an MEA is a requirement for submission.
In April 2019, a national registry was established in Taiwan for patients undergoing immunotherapy (17). Clinical characteristics, treatment duration, toxicity, and the outcome of the postcheckpoint inhibitor treatments were recorded. RWD indicated the health benefits experienced in a clinical setting, suggesting that immunotherapy is gaining recognition (17). RWD and evidence within a certain duration after NHI reimbursement are warranted and should be evaluated by the CDE/HTA.
This paper demonstrates that Taiwan's immune checkpoint inhibitors registry database is a model for systemically developing real-world evidence of the effectiveness and safety of novel interventions with engagement from the government. HTA sits within a systematic evidence-based medicine framework (Reference O'Rourke, Oortwijn and Schuller23). By analyzing RWD, we can understand the therapeutic effects of IO treatment in Taiwanese patients, thereby enabling payers to adjust payment regulations and scope (16). Compared with clinical trial data, RWD may be considered a better representation of local patient demographics as it is more reflective of clinical practice and potentially more closely aligned with contemporary treatment patterns (Reference Bullement, Podkonjak, Robinson, Benson, Selby and Hatswell24).
With an HTA, patient access to high-cost medicines that improve health outcomes is possible (Reference Hasan, Lu, Babar and Babar13). HTAs can ensure value for financial investments in high-cost medicines, given limited healthcare resources (Reference Hasan, Lu, Babar and Babar13). However, uncertainties often occur related to the clinical evidence and/or financial impacts of high-cost medicines (Reference Wenzl and Chapman25). Therefore, to restrict the effects of uncertainty, MEAs, also known as patient access schemes, have been introduced (Reference Hasan, Lu, Babar and Babar13). MEAs represent contractual agreements between the manufacturers and healthcare payers that allow for market access to high-cost medicines (Reference Hasan, Lu, Babar and Babar13).
Taiwan's government is responsible for public health and health care and encourages early market introduction of new drugs with enhanced efficacy and safety. However, the government must also ensure the sustainable development of the NHI system. Thus, the NHIA is continuously researching how to optimize the system's financial risk-sharing mechanism so that new high-value, and by extension high-cost, medical technologies can be covered by the insurance system.
Based on the multiyear price–volume agreement (PVA) program, we are currently working out an MEA that is suitable for Taiwan's healthcare system. In the future, in addition to examining the financial impact of new drugs on the healthcare system, we will also take into account (i) patient feedback regarding the value of the drug, (ii) the financial risks shared by pharmaceutical manufacturers, and (iii) the international pricing layout of their pharmaceutical products. Several financially based schemes (e.g., MEAs) have been proposed in Taiwan. However, there are challenges, including how to calculate a reasonable rebate and what adjustments need to be made to the original agreement when the MEA drug has been approved for an indication.
Given the financial pressures faced by the NHI, the challenges associated with making decisions to subsidize high-cost medicines are here to stay. The contractual agreements between manufacturers and healthcare payers are particularly challenging because the financially based ones are confidential, so it is difficult to learn from other countries’ experiences and define what could be considered an ideal contract.
The importance of fair and transparent decision making and the consideration of patients and public preferences about the availability of high-cost medicines are likely to become increasingly prominent (Reference Wenzl and Chapman25;Reference Weale, Kieslich, Littlejohns, Tugendhaft, Tumilty and Weerasuriya26).
Conclusion
Healthcare expenditures have increased rapidly and manifold in most countries. In light of the high costs of medicine, every country faces challenges. Taiwan chose to implement a policy for high-cost medicines and to use MEAs to establish a national registry for immunotherapy patients in Taiwan. This policy was implemented in April 2019, and in the year since, more than 1,000 patients have been reimbursed for treatment with these IO drugs, and the budget has been controlled within the originally set range. The challenge we are now facing is expanding indications and combination regimens of these IO drugs within the same budget as last year. Also, in the face of poor treatment efficacy, how will payers balance the pressures from patients and manufacturers and the trade-off between resource and priority.
The role of an HTA is to draw upon the evidence to support policy making. Evidence to date indicates that Taiwan's reimbursement policy for such therapies is beneficial for patients, clinical personnel, NHIA stakeholders, and the industry. In the coming years, close monitoring and evaluations will be required to analyze the effects of the current IO treatment with an inevitable trade-off between expenditures and access.
Introduction
Oncology treatments have shifted from chemotherapy to targeted therapies and, more recently, to immuno-oncology (IO). Novel IO drugs such as ipilimumab, pembrolizumab, nivolumab, and atezolizumab inhibit tumor-induced immune suppression and enable the immune system to fight cancer (Reference Shergold, Millar and Nibbs1;Reference Nishijima, Shachar, Nyrop and Muss2). These medical advancements, coupled with the growing prevalence of cancer, have led to costs spiraling out of control (Reference Dranitsaris, Zhu, Adunlin and Vincent3). In many countries, including Taiwan, as IO therapy becomes the new standard of care in various tumor treatments, the extraordinarily high costs of these IO drugs have resulted in a tremendous challenge for both public and private healthcare systems (Reference Dranitsaris, Zhu, Adunlin and Vincent3).
In Taiwan, cancer is a leading cause of death (4). In 2018, approximately 206.9 out of every 100,000 Taiwanese died from malignant neoplasms, compared with 91.5 out of every 100,000 Taiwanese who died from heart disease (4). According to the National Health Insurance Administration (NHIA), approximately 720,000 patients sought medical treatment for cancer in 2018, indicating an annual increase of 4.14 percent (5). Meanwhile, the total expenses for cancer treatment, including the cost of drugs, examinations, tests, and in-patient care, reached NT$104.5 billion (≈US$3.5 billion), indicating an annual increase of 7.47 percent (5).
Since its implementation in 1995, Taiwan's National Health Insurance (NHI) program has successfully offered universal health coverage to all citizens at affordable costs (Reference Wu, Majeed and Kuo6). Taiwan's NHI is characterized by mandatory enrollment for all citizens, a single-payer government-run insurer, and comprehensive benefits coverage. As of 2014, more than 99 percent of Taiwan's population had enrolled, and this high coverage level has been maintained since then (Reference Wu, Majeed and Kuo6).
The NHI plays a crucial role in safeguarding the nation's health. Although the listing and reimbursing of IO drugs is critical for cancer patient treatments, the drastic increase in cancer prevalence and novel cancer immunotherapy drugs has significantly increased the NHI's financial burden (5). According to IQVIA's 2019 global oncology report, the total cost of oncology drugs in the United States increased from US$29.4 billion to US$56.7 billion between 2013 and 2018 (7). Meanwhile, in Taiwan, the total cost of oncology drugs increased from NT$29 billion (≈US$0.9 billion) to NT$40 billion (≈US$1.3 billion) between 2014 and 2018 (5;8).
New drugs for cancer immunotherapy are costly; for example, classical Hodgkin's lymphoma treatment costs approximately NT$2 million (≈US$66,801) per person (9). This new class of drugs for cancer immune checkpoints also has a wide range of indications. Consequently, the number of potential patients under the indications has increased. If complete coverage were granted, the cost would be nearly NT$6 billion (≈US$198 million), which would push other essential items out of the NHI budget (9).
High-Cost Medicine Policy in Taiwan
In order to enhance the accessibility to advanced therapy, Taiwan's NHIA announced two pathways for high-cost medicines: a managed entry agreement (MEA) and a set of general rules for reimbursement submission for high-cost drugs (10).
Taiwan started conducting a Health Technology Assessment (HTA) in 2007 to support the NHIA in its reimbursement selection, focusing mainly on introducing new drugs into the NHI system, and has continued it ever since. The Division of HTA in the Center of Drug Evaluation, Taiwan (CDE/HTA), was authorized by the Ministry of Health and Welfare (MOHW) to support the HTA program (Reference Kao, Huang, Wu and Gau11). As per the NHIA's request, the CDE/HTA reviewed the MEA programs of other countries in 2017 and also, between 2015 and 2017, conducted clinical and economic assessments of four IO immune checkpoint inhibitors to facilitate policy making (10). In 2017, the International Network of Agencies for HTA (12) revealed that pembrolizumab, nivolumab, and ipilimumab were reimbursed for malignant melanoma or nonsmall cell lung carcinoma in the UK, Canada, Germany, Austria, Spain, and Australia (12). There are various mechanisms in place to share the treatment costs and risks of treatment failure as well as reduce the overall impact of these high-cost drugs on healthcare expenditures (12). The MEA program is one of the most popular mechanisms (Reference Hasan, Lu, Babar and Babar13). Consequently, in September 2018, the MOHW announced the addition of relevant regulations to the MEA (14). Under the authorization of the regulations, the NHIA applied multiple negotiation mechanisms for reaching consensus with marketing authorization holders (14) to accelerate the introduction of good new medicines so that patients can get more timely treatment and care.
After a series of stakeholder meetings and communications in 2018, the NHIA proposed a set of general rules of reimbursement submission for high-cost drugs. The key principles are as follows (10):
(1) High-cost drugs are defined as drugs with expenditures exceeding NT$500 million (≈US$16.6 million) per annum.
(2) Objective, clear, and measurable efficacy end points and evaluation methods must be provided.
(3) A list of side effects and the estimated costs of managing them must be provided.
(4) An approved indication that has been reimbursed in a reference country (Canada, Australia, or the UK) must be included.
(5) An MEA model and related regulations must be proposed.
(6) A Taiwanese pharmaco-economic analysis to support the cost-effectiveness must be provided along with a financial analysis report.
In 2017, the CDE/HTA conducted a review of IO drugs’ safety using model simulations and estimated the eligible user population and costs. The results of the research were adopted and referenced by the NHIA and Pharmaceutical Benefits and Reimbursement Scheme (PBRS) (9). As indicated in the assessment by the CDE/HTA and documentation submitted by the manufacturers, new drugs for cancer immunotherapy are costly at approximately NT$2 to $4 million (≈US$67,000 to $134,000) per person per year (9;15). In addition, the new cancer immune checkpoint drugs have a very wide range of indications, leading to an increase in the number of potential users. As already mentioned, complete coverage could push other items out of the NHI budget (9;15). Thus, to manage the impact on NHI finances of new drugs for cancer immunotherapy, the PBRS Committee held many meetings and ultimately reached a consensus with high-level NHIA officers that new inhibitory drugs for cancer immune checkpoints would be added to NHI coverage with an upper limit of NT$800 million (≈US$26.7 million) in the year 2019 (9;15). The outcomes of using the new immunotherapy drugs have varied widely depending on the type of cancer (9). Based on a drug fee estimate of NT$1 million per person per year, the NT$800 million (≈US$26.7 million) budget for 2019 could support roughly 800 cancer patients (15). The cost of treatment per person for every 4 weeks is estimated to be around NT$176,600 (≈US$5,886). If any of the budget remains due to patients not completing their treatment for any reason, then additional patients could be added (15).
Coverage and reimbursement decisions for expensive medicines should be based on scientific evidence, especially value-based pharmaco-economic evaluations and engaging stakeholders in the process, to account for patient and public preferences (Reference Hasan, Lu, Babar and Babar13). The NHIA also set up a patient registry system to collect real-world data (RWD) from patients using the cancer immune checkpoints (15). The CDE/HTA assessed the RWD to inform decision making at different levels of the healthcare system, and the NHIA thereafter published an executive summary on its Web site (15). On 1 April 2019, the NHIA covered three IO drugs—atezolizumab, pembrolizumab, and nivolumab—for eight diseases and the following ten indications (16):
(1) Unresectable or metastasized melanoma stage 3 or 4;
(2) Second-line drug for advanced squamous cells of nonsmall cell lung cancer;
(3) Third-line drug for advanced nonsmall cell lung cancer;
(4) First-line drug for metastasized nonsmall cell lung cancer;
(5) Classical Hodgkin's lymphoma;
(6) Failed platinum-based chemotherapy and local advanced unresectable or metastasized urothelial carcinoma with disease progression;
(7) Metastasized urothelial carcinoma that cannot be treated with chemotherapy;
(8) Metastasized gastric adenocarcinoma for which second-line or advanced chemotherapy has failed;
(9) Recurrent or metastasized head and neck squamous cell carcinoma;
(10) Advanced or metastatic hepatocellular carcinoma.
Additional novel immunotherapy drugs for cancer that become covered by the NHI or any changes in the requirements will be announced by NHIA (16).
As indicated by the results of some clinical trials, considerable uncertainty remains regarding the effectiveness and safety of these new IO drugs, and the cost-effectiveness is still unclear. Moreover, some of the trials specified a maximum treatment duration of 24 months (16). Thus, to provide all eligible patients a fair treatment opportunity, the maximum coverage period is determined to be 52 weeks (16). Patients using immune checkpoint inhibitors must be evaluated every 12 weeks. Those exhibiting a complete or partial response to the therapy may continue using the drugs, whereas those presenting progressive disease or exhibiting moderate, severe, or life-threatening adverse reactions should immediately cease using the IO (16). Finally, considering the common side effects of new drugs in cancer immunotherapy, only patients with normally acceptable cardiopulmonary, liver, and kidney functionality may use them (16).
Taiwan implemented a precertification mechanism for reimbursing these new immunotherapy drugs, and physicians must upload the following patient information to the precertification page on the NHI virtual private network (16):
(1) Physical status and the results of cardiopulmonary, liver, and kidney function tests;
(2) Programmed death-ligand 1 (PD-L1) expression reports signed by pathologists;
(3) Treatment protocol, including out-of-pocket expenses for chemotherapies or targeted therapies;
(4) Related medical records and images, as well as other necessary documents.
To increase the effectiveness of new drugs, the PBRS decided that coverage priority should be given to patients with high levels of PD-L1 expression because some pivotal trials have shown that such patients are more likely to present improved drug responses (16). For instance, to prescribe pembrolizumab as a second-line drug for nonsmall cell lung cancer, a test report must be attached with Dako 22C3 or Ventana SP263 as the testing instrument showing a PD-L1 expression level of ≥50 percent. For nivolumab to be prescribed as a second-line drug for nonsmall cell lung cancer, a test report must be attached with Dako 28-8 as the testing instrument and a PD-L1 expression level of ≥50 percent. To prescribe atezolizumab as a second-line drug for nonsmall cell lung cancer, a test report must be attached with Ventana SP142 as the testing instrument and a PD-L1 expression level of ≥50 percent on tumor cells or ≥10 percent on tumor-infiltrating cells. All test reports must be signed by a pathologist (16).
In addition, all of the aforementioned regulations reimbursing immune checkpoint inhibitors should be reviewed every 3 months, according to the RWD collected through the precertification mechanism. As of March 2020, a total of 1,490 patients had been accepted for IO treatment and included in the register database (17). Among the 1,154 analyzable cases, approximately 21.1 percent (243/1,154) had a complete or partial response (17). Adverse events were reported and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE). Among 849 analyzable cases, approximately 9.4 percent (80/849) reported immune-related adverse events and 3.9 percent (33/849) discontinued treatment because of side-effects (as of March 2020) (15). For stakeholders’ reference, the NHIA publishes all information in Mandarin (17).
To effectively use the healthcare resources, the reimbursement policy for IO drugs was updated in March 2020. Initially, three IO drugs reimbursed by the NHIA—atezolizumab, pembrolizumab, and nivolumab—received extended coverage from 1 to 2 years, excluding advanced or metastatic hepatocellular carcinoma and metastasized gastric adenocarcinoma because of lower rates of effectiveness with those cancers in Taiwan (16).
Discussion
Over the last 5 years, the introduction of a new class of drugs (IO drugs) has dramatically changed the treatment of various cancers, including lung cancer (Reference Pasello, Pavan, Attili, Bortolami, Bonanno and Menis18). However, despite the increases in overall survival rates seen in some clinical trials, the majority of patients have shown primary resistance and have not benefitted from these agents (Reference Oliva, Spreafico, Taberna, Alemany, Coburn and Mesia19), especially considering the potentially severe immune-related toxicities and their high costs (Reference Oliva, Spreafico, Taberna, Alemany, Coburn and Mesia19). Taiwan is not alone in facing challenges related to rationing and prioritizing access to high-cost medicines; such issues present challenges for all countries. Since 2015, the CDE/HTA team has conducted systematic reviews, as well as clinical and economic assessments, of four IO drugs in the class of immune checkpoint inhibitors to provide evidence for policy-making decisions. However, the outcomes and financial impacts of high-cost medicines remain uncertain. Some countries have implemented MEAs to share the cost of uncertainty between the payer and the marketing authorization holder, thereby facilitating access to new high-cost medicines (Reference Jommi and Babar20). Other countries allow payers to set up special access schemes by allocating funds for nonpublicly reimbursed high-cost medicines (Reference Aggarwal, Fojo, Chamberlain, Davis and Sullivan21), such as the Cancer Drugs Fund established in England in 2010 (Reference Aggarwal, Fojo, Chamberlain, Davis and Sullivan21). A newer approach involves the collection of additional data during a managed access period when patients can access the treatment (Reference Ferrario and Kanavos22). These additional data help policy makers decide whether new treatments should be routinely funded (Reference Ferrario and Kanavos22).
In June 2018, Taiwan established a new policy for submitting novel oncology drugs for consideration of NHI coverage. These general rules of reimbursement of submission for high-cost drugs cover cancer drugs with annual expenditures exceeding NT$500 million (≈US$16.6 million), although an MEA is a requirement for submission.
In April 2019, a national registry was established in Taiwan for patients undergoing immunotherapy (17). Clinical characteristics, treatment duration, toxicity, and the outcome of the postcheckpoint inhibitor treatments were recorded. RWD indicated the health benefits experienced in a clinical setting, suggesting that immunotherapy is gaining recognition (17). RWD and evidence within a certain duration after NHI reimbursement are warranted and should be evaluated by the CDE/HTA.
This paper demonstrates that Taiwan's immune checkpoint inhibitors registry database is a model for systemically developing real-world evidence of the effectiveness and safety of novel interventions with engagement from the government. HTA sits within a systematic evidence-based medicine framework (Reference O'Rourke, Oortwijn and Schuller23). By analyzing RWD, we can understand the therapeutic effects of IO treatment in Taiwanese patients, thereby enabling payers to adjust payment regulations and scope (16). Compared with clinical trial data, RWD may be considered a better representation of local patient demographics as it is more reflective of clinical practice and potentially more closely aligned with contemporary treatment patterns (Reference Bullement, Podkonjak, Robinson, Benson, Selby and Hatswell24).
With an HTA, patient access to high-cost medicines that improve health outcomes is possible (Reference Hasan, Lu, Babar and Babar13). HTAs can ensure value for financial investments in high-cost medicines, given limited healthcare resources (Reference Hasan, Lu, Babar and Babar13). However, uncertainties often occur related to the clinical evidence and/or financial impacts of high-cost medicines (Reference Wenzl and Chapman25). Therefore, to restrict the effects of uncertainty, MEAs, also known as patient access schemes, have been introduced (Reference Hasan, Lu, Babar and Babar13). MEAs represent contractual agreements between the manufacturers and healthcare payers that allow for market access to high-cost medicines (Reference Hasan, Lu, Babar and Babar13).
Taiwan's government is responsible for public health and health care and encourages early market introduction of new drugs with enhanced efficacy and safety. However, the government must also ensure the sustainable development of the NHI system. Thus, the NHIA is continuously researching how to optimize the system's financial risk-sharing mechanism so that new high-value, and by extension high-cost, medical technologies can be covered by the insurance system.
Based on the multiyear price–volume agreement (PVA) program, we are currently working out an MEA that is suitable for Taiwan's healthcare system. In the future, in addition to examining the financial impact of new drugs on the healthcare system, we will also take into account (i) patient feedback regarding the value of the drug, (ii) the financial risks shared by pharmaceutical manufacturers, and (iii) the international pricing layout of their pharmaceutical products. Several financially based schemes (e.g., MEAs) have been proposed in Taiwan. However, there are challenges, including how to calculate a reasonable rebate and what adjustments need to be made to the original agreement when the MEA drug has been approved for an indication.
Given the financial pressures faced by the NHI, the challenges associated with making decisions to subsidize high-cost medicines are here to stay. The contractual agreements between manufacturers and healthcare payers are particularly challenging because the financially based ones are confidential, so it is difficult to learn from other countries’ experiences and define what could be considered an ideal contract.
The importance of fair and transparent decision making and the consideration of patients and public preferences about the availability of high-cost medicines are likely to become increasingly prominent (Reference Wenzl and Chapman25;Reference Weale, Kieslich, Littlejohns, Tugendhaft, Tumilty and Weerasuriya26).
Conclusion
Healthcare expenditures have increased rapidly and manifold in most countries. In light of the high costs of medicine, every country faces challenges. Taiwan chose to implement a policy for high-cost medicines and to use MEAs to establish a national registry for immunotherapy patients in Taiwan. This policy was implemented in April 2019, and in the year since, more than 1,000 patients have been reimbursed for treatment with these IO drugs, and the budget has been controlled within the originally set range. The challenge we are now facing is expanding indications and combination regimens of these IO drugs within the same budget as last year. Also, in the face of poor treatment efficacy, how will payers balance the pressures from patients and manufacturers and the trade-off between resource and priority.
The role of an HTA is to draw upon the evidence to support policy making. Evidence to date indicates that Taiwan's reimbursement policy for such therapies is beneficial for patients, clinical personnel, NHIA stakeholders, and the industry. In the coming years, close monitoring and evaluations will be required to analyze the effects of the current IO treatment with an inevitable trade-off between expenditures and access.
Acknowledgments
The authors want to thank the Ministry of Health and Welfare (MOHW) and the National Health Insurance Administration (NHIA) for their financial support through Research Grant No. 1070077726.
Funding
No funding support was provided for the final preparation of this manuscript.
Disclosures
Li Ying Huang has nothing to disclose and has no conflicts of interest, financial or otherwise.
Churn-Shiouh Gau has nothing to disclose and has no conflicts of interest, financial or otherwise.