The value-for-money assessment and funding arrangements for high-priced drugs in an era of uncertainty: a comparative analysis of national health technology assessment agencies in South Korea, England, Australia, and Canada.

Introduction

In recent years, innovative health technologies have emerged as a promising solution for patients with untreatable or challenging conditions, such as advanced cancer and genetic rare diseases. However, these technologies often come with high costs, driven by the complexity of development and the small number of patients they target. For example, Zolgensma, a one-time-only gene therapy treatment for spinal muscular atrophy, was introduced with a list price of £1.795 million in the UK [ 1 ], $2.1 million in the US [ 2 ], and similar prices in other non-Western countries like South Korea. Even more expensive treatments, such as Lenmeldy for metachromatic leukodystrophy and Beqvez for haemophilia B, are on the way to global markets [ 3 ]. Despite such high price tags, payers face significant political pressure to provide early patient access to these technologies, given the high unmet needs of patients with such conditions.

However, the payer’s dilemma is further complicated by the uncertainty surrounding the clinical and economic value of these technologies. Clinical evidence supporting their benefits is often limited at the time of launch, with data frequently derived from low-quality sources such as single-arm or non-randomised trials, which commonly involve a small number of patients and provide immature evidence. Moreover, this uncertainty is often amplified by new market authorisation pathways introduced by regulatory bodies to expedite access to these technologies [ 4 – 6 ]. Therefore, it remains unclear whether the claimed but unproven long-term benefits of these innovative technologies can eventually justify their high prices.

Balancing timely patient access with uncertainty tolerance presents a formidable challenge. Given the substantial cost implications of incorrect coverage decisions-particularly for high-priced drugs-it is crucial to adopt more effective strategies to assess and address these uncertainties. Focusing on high-priced drugs with limited evidence introduced between 2015 and 2022 through the cost-effectiveness analysis (CEA) waiver track in South Korea-a specific pathway designed to facilitate the introduction of such therapies-this study examines how these drugs were introduced, appraised, and how the associated uncertainties were addressed by national HTA agencies in England, Australia, and Canada, with a particular focus on managed entry agreements (MEAs), in comparison to South Korea.

Country background: HTA and MEA policy

Many countries have adopted multi-layered strategies, including MEAs, to address the challenges of introducing high-priced drugs with limited evidence. MEAs encompass a range of arrangements that impose specific conditions on the coverage of new health technologies [ 7 – 11 ]. These agreements are negotiated between manufacturers and payers or authorities responsible for pricing or coverage decisions. MEAs have also been referred to by other terms, such as risk-sharing arrangements, with the terminology varying across countries. This variation often reflects the primary policy objectives the agreements aim to achieve or the specific nature of the agreements themselves [ 12 ]. MEAs are generally classified into two main categories: financial-based agreements and performance-based agreements (see Appendix 1 for the taxonomy of MEAs, available as online supplementary information). Performance-based agreements are further divided into two subcategories: outcome-linked payments and coverage with evidence development.

In this section, country-specific terms are used to better align with each nation’s policy objectives. However, for clarity and consistency, the term ‘MEAs’ is used throughout other sections as an umbrella term.

South Korea

South Korea adopted a positive listing system in 2006, requiring manufacturers to submit CEA data to justify their prices and list new drugs on the national health insurance formulary at higher prices. The Health Insurance Review and Assessment Service (HIRA) evaluates the submissions and makes reimbursement recommendations primarily based on clinical effectiveness and cost-effectiveness.

In 2013, the Korean government introduced a risk-sharing agreement to provide early patient access to drugs targeting high unmet needs, such as those treating rare, life-threatening conditions with limited therapeutic alternatives. The RSA has several subtypes, including refunds, expenditure caps, utilisation caps per patient, free initial treatment, and outcome-based pricing arrangements, with refunds being the most prevalent type. RSA drugs are still subject to submitting CEA data for price premiums.

To address difficulties in generating robust evidence for CEA that were claimed to create patient access delays for some essential drugs, the government further introduced a CEA waiver policy in 2015. Anticancer or orphan drugs targeting a small number of patients can benefit from this policy if they meet the following criteria [ 13 ]: 1) limited treatment options, 2) difficulties generating robust evidence (e.g., data obtained from single-arm trials), and 3) listed in three or more of the reference countries (A7 countries: France, Germany, Italy, Japan, Switzerland, the United Kingdom, and the United States [currently A8 with the addition of Canada in December 2022]) [ 13 ]. However, it is not clearly outlined in publicly available documents how their (additional) clinical benefits are assessed or with what degree of rigor. Since no CEA data are available to justify the price premiums for these drugs due to the CEA waiver policy, their prices are largely based on reference country pricing. Drugs introduced under this CEA waiver policy are currently subject to risk-sharing agreements, typically involving expenditure caps and, in some cases, additional requirements.

England

In England, the National Institute for Health and Care Excellence (NICE) is responsible for conducting technology appraisals and providing guidance for the routine commissioning of new drugs at the National Health Service (NHS). NICE operates several HTA programs, including the primary technology appraisal program established in 1999 and the dedicated highly specialised technologies program established in 2013. The highly specialised technologies programme evaluates technologies for very rare diseases, significantly shortening life or severely impairing quality of life, which have a small number of patients, limited or no treatment options, and difficulties with collecting evidence [ 14 ].

NICE typically applies a cost-effectiveness threshold of £20,000–30,000 per quality-adjusted life year (QALY) gained, while also explicitly considering severity as a modifier, with QALY weights ranging from 1 to 1.7 [ 15 ]. For highly specialised technologies, NICE applies a cost-effectiveness threshold of £100,000, with the size of benefits (i.e., incremental QALYs gained) as a modifier, ranging from QALY weights of 1 to 3 as the magnitude of benefit increases [ 15 ].

The patient access scheme is a key type of MEA in England, primarily used to improve the cost-effectiveness of drugs [ 16 , 17 ]. The patient access scheme can take two forms: simple patient access scheme, which involves confidential fixed prices or percentage discounts (the preferred option), and complex patient access scheme, such as outcomes-based caps or upfront free stock, used only in exceptional circumstances.

Commercial access agreements are another form of MEA, focusing on pricing agreements. They are used when companies propose an enhanced value offer and when launching the product commercially would be challenging. Unlike complex patient access scheme, commercial access agreements are confidential and include arrangements like budget caps, price/volume agreements, or outcome-based agreements.

Managed access agreements function as coverage with evidence development. These agreements are employed when there are significant clinical and financial uncertainties at the time of appraisal. Managed access agreements consist of two key components: a data collection agreement and a funding agreement. Drugs under managed access agreements are mostly funded through the Cancer Drugs Fund or the Innovative Medicines Fund, with NHS England allocating annual budgets of £340 million for each Fund [ 18 ]. Interim guidance and recommendations are updated based on new evidence collected during the managed access period. Further details are available in Table 1 (Appendix 1, online supplementary information).

Australia

In Australia, the Pharmaceutical Benefits Advisory Committee (PBAC) is responsible for assessing HTA submissions and providing recommendations on which medicines to subsidise and list on the Pharmaceutical Benefits Scheme formulary, a national scheme for drug reimbursement [ 19 ]. Notably, some gene therapies (e.g., Kymriah [Tisagenlecleucel]), can be appraised by the Medical Services Advisory Committee (MSAC) because they involve both a drug component and a treatment procedure. Unlike England, no explicit threshold has been acknowledged in Australia, although available evidence suggests an implicit threshold of about AUD$ 50,000 per additional QALY gained [ 20 ].

In 2010, the Australian Government introduced a managed entry scheme to improve patient access to Pharmaceutical Benefits Scheme-subsidised drugs and enhance the quality of evidence provided to decision-makers [ 21 ]. It is a flexible subsidisation arrangement to reimburse promising drugs, typically conditional on further evidence collation. Moreover, the Australian Government has further developed several mechanisms that can be described as MEAs [ 22 ]. Evidence suggests that the majority of MEAs in Australia are financial-based agreements, which generally include discounts or reimbursement caps [ 22 ].

There is also a special funding program called the Life Saving Drugs Program, which operates in exceptional circumstances [ 23 ]. The program provides fully subsidised access to expensive essential drugs that are clinically effective but not cost-effective, as evaluated by PBAC, for patients with ultra-rare and life-threatening diseases.

Canada

The HTA and pricing negotiations process is somewhat complex in Canada. HTA is conducted at the federal level, a prerequisite for public funding through provincial healthcare systems, but final pricing and reimbursement decisions are made at the provincial level. The Canadian Agency for Drugs and Technologies in Health (CADTH), a pan-Canadian HTA agency, reviews HTA data on behalf of all provinces and territories except Quebec. It has two centralised review processes for new drugs: the Common Drug Review (CDR) for non-oncology drugs and the pan-Canadian Oncology Drug Review for oncology drugs (pCODR). CADTH typically considers CAD 50,000 per QALY gained as a cost-effectiveness threshold [ 24 , 25 ].

After CADTH issues a positive recommendation, public drug plans collectively negotiate pricing with the manufacturer through the pan-Canadian Pharmaceutical Alliance, leveraging the combined purchasing power of the provinces [ 26 ]. While CADTH provides recommendations and pricing conditions, the provinces use this information or advice to negotiate pricing arrangements, including MEAs. However, details about such arrangements are limited in the public domain.

As of May 1, 2024, CADTH’s operating name changed to Canada’s Drug Agency. Since all data and work presented here were obtained before this change, the name CADTH is used throughout this paper.

Materials and methods

Sample selection

This study focused on a specific subset of high-priced drugs introduced through the CEA waiver track in South Korea to compare how these drugs were introduced and appraised by national HTA agencies in England, Australia, and Canada, in comparison to South Korea. These drugs specifically target a small patient population and are characterised by significant uncertainties surrounding their clinical and economic values due to limited evidence at the time of launch.

A list of high-priced drugs, defined as those with an average per-patient annual expenditures of at least KRW 10,000,000 in 2021 equivalent to $11,708 (2021 purchasing power parity [ 27 ]) were first obtained from the National Health Insurance Service in 2022, at the time of this research [ 28 ]. The definition of ‘high-priced drugs’ was deliberately made inclusive, as no clear cut-off point emerged in the spending pattern. Of the 178 high-priced drugs identified, 20 were introduced through the CEA waiver track, with an average per-patient annual expenditure of KRW 43,000,000 ($50,346 in 2021 purchasing power parity) in 2021. In addition to these 20 drugs, the study further included two major one-shot gene therapies (Onasemnogene and Tisagenlecleucel), although they did not have records of 2021 annual expenditures. These two therapies were introduced in 2021 and 2022, respectively, at record-high prices through the CEA waiver policy. Overall, the final analysis included 22 drugs with 24 indications, introduced over the past years (see Appendix 2, online supplementary information).

Besides South Korea, England, Australia, and Canada were carefully selected for this study because of their long-established HTA policies and processes that guide coverage decisions [ 29 ]. These countries employ similar appraisal approaches, focusing on clinical effectiveness and cost-effectiveness. Despite differences in implementation, they commonly rely on these principles, and their HTA reports-available in English-are actively shared, facilitating comparisons across agencies.

Data source

This study collected data from appraisal documents published by national HTA agencies, including HIRA (South Korea) [ 30 ], NICE (England) [ 31 ], PBAC and partially MSAC (Australia) [ 23 , 32 , 33 ], and CADTH (Canada) [ 34 ]. These documents contained committee deliberations and relevant publicly available information. When multiple appraisal documents from the same HTA agency were available for the selected drug-indication, data were sourced from the final appraisal document available. Follow-up actions after 2022 or unrecorded in appraisal documents were excluded.

Supplementary documents from these agencies were reviewed when the information in the appraisal documents was unclear, to ensure data accuracy and completeness. For drugs with multiple indications appraised in South Korea, each indication was treated as an independent drug-indication pair count to account for variations in the evaluation process. If additional clinical information was needed, trial publications and ClinicalTrials.gov were searched to supplement the data extracted from the appraisal documents.

Data extraction

This study focused on 1) the type of coverage recommendations and MEA contracts; 2) clinical and economic evidence considered; and 3) whether and how data collection was processed to address uncertainty.

Specifically, the following information was extracted: the date of the appraisal, coverage recommendations, types of MEA contracts and other schemes (if data are available), the study designs of key clinical evidence considered (e.g., randomised controlled trials [RCTs], single-arm trials, other sources: classified as RCT > single-arm > other if multiple sources are available), sources of comparative evidence (e.g., head-to-head RCT, indirect comparison, simple citation/expert opinions, no comparative data available [i.e., alternatives reported but their comparative evidence not described], no alternatives available reported/mentioned), median follow-up and overall survival of primary clinical trials considered, types of economic evidence (e.g., CEA, cost-minimisation analysis, simple cost comparison, external reference pricing, other), types of uncertainty reported (efficacy-related, safety-related, other types, not reported), data collection requirements, types of data required for the collection, and sources of data collection.

To ensure the accuracy of the extracted data, two reviewers (SC and JL) independently assessed the full text of each appraisal document and discussed any uncertainties or discrepancies until reaching a consensus among all authors.

Results

Coverage recommendations and MEA status for high-priced drugs

Table 1 compares coverage recommendations and MEA status for 22 high-priced drugs across 24 indications in South Korea, England, Australia, and Canada. In South Korea, all but two drugs (Brentuximab vedotin and Ceritinib) were subject to expenditure caps, which served as a default control mechanism (since late 2016) for drugs introduced via the CEA waiver policy. Over time, additional tools were further applied to CEA-waiver drugs, especially for those presenting greater affordability and uncertainty challenges. These measures included free initial treatment (1 drug-indication pair), refunds (8 pairs), and, most recently, outcome-linked refunds for two one-shot gene therapies (3 pairs).

Most of these high-priced drugs were formally appraised and introduced in other countries, primarily through MEAs. In England, 18 drugs (20 drug-indication pairs) were appraised by NICE, all of which were introduced through MEAs, except for Vandetinib, which received a negative recommendation. The most common type of MEA was the patient access scheme (all involving simple discounts), applied to 16 pairs (80.0%), either alone or in combination with other components. The managed access agreement, which requires further data collection, was applied to about half of the pairs ( n = 11). These managed access agreement drugs were introduced either through the Cancer Drug Fund (7 pairs) or highly specialised technology programmes (3 pairs: Elosulfase alfa, Asfotase alfa, and Onasemnogene), except for Nusinersen. Regardless of the pathway, all managed access agreement drugs were subject to additional control measures-the patient access scheme and/or commercial access agreements-during the managed access period for data collection.

Four drugs were not appraised by NICE. Of these, Olmutinib and Tafamidis meglumine (with an indication studied) were not appraised in any other countries but South Korea. Olmutinib was developed and appraised only in South Korea, while Tafamidis meglumine was appraised for a different indication in other countries. Defibrotide, without a NICE appraisal, was made available through special commissioning by NHS England in designated specialised centres [ 35 ]. While Siltuximab, a cancer drug, was available in England, its technology appraisal information was unavailable.

In Australia, 17 high-priced drugs (19 pairs) were formally appraised by PBAC/MSAC (2 drugs, Lutetium oxodotreotide and Kymriah with MSAC), and of these, 14 (16 pairs, 84.2%) were positively recommended for use. Notably, although Elosulfase alfa and Asfotase alfa initially received negative recommendations, they were later made available to patients through a special funding program, the Life Saving Drugs Program [ 36 ]. These two drugs also happened to be introduced through the highly specialised technology programs in England. Of the 16 pairs that received positive recommendations, all but three were introduced through some form of MEAs, although their details were less explicit than in England. The most common type of MEA was expenditure/volume caps ( n = 7), which were sometimes applied to a group of drugs with the same indication. For instance, the caps for Niraparib were included in the caps imposed on Olaparib, which shared the same indication of recurrent ovarian cancers. Data collection was also required for 4 pairs (2 gene therapies and Trametinib with the managed entry scheme) but their details were not available.

In Canada, CADTH appraised 20 out of 24 pairs, and none received a negative recommendation. However, CADTH recommended all these pairs with price adjustment conditions to meet cost-effectiveness standards in the Canadian healthcare system. Some pairs also had additional conditions, such as conditional treatment continuation (Elosulfase alfa and Asfotase alfa) and data collection (4 pairs including Elosulfase alfa, Nusinersen, and Tisagenlecleucel). Although these recommendations are not legally binding, they can guide regional decision-makers in price negotiations. Notably, for a recently introduced gene therapy (Tisagenlecleucel), CADTH explicitly urged the creation of interprovincial agreements to ensure equitable patient access across all jurisdictions [ 37 ].

Clinical and economic evidence considered in the appraisal of high-priced drugs

Table 2 provides an overview of the clinical and economic evidence used to appraise high-priced drugs by HTA committees in four countries. The primary source of clinical evidence was predominantly RCTs, accounting for 50.0% in South Korea and up to 70.0% in Canada. A significant proportion of evidence also relied on single-arm trials, ranging from 30.0% in Canada to 41.7% in South Korea.

While the primary source of clinical evidence was generally consistent across HTA agencies, notable differences emerged in the reporting of median follow-up and overall survival. These variations were mainly attributed to differences in reporting practices and data cut-off points. South Korea had the lowest frequency of median follow-up reporting, with 70.8% of cases not including this data. However, other countries also had relatively high rates of non-reporting, ranging from 35.0% in Canada to 57.9% in Australia. Non-reporting of median overall survival, though less frequent, was also notable in South Korea and Australia. Despite the high prices of these life-saving drugs, only a small percentage (ranging from 10% in Canada to 25.0% in England) reported a median overall survival of at least 2 years.

Comparative effectiveness assessments, which directly or indirectly compare the drugs under appraisal with their selected comparators, revealed significant discrepancies across countries, particularly between South Korea and the other three. In South Korea, nearly half of the appraisals (45.8%) relied on expert opinions or citations, and one-third (33.3%) lacked comparative data. This was primarily because HIRA often concluded that no therapeutically equivalent drugs were available, focusing on identifying the presence of additional clinical benefits rather than quantifying their magnitude. In contrast, the other three countries showed greater reliance on head-to-head RCT data (ranging from 30.0% in England to 45.0% in Canada and 47.4% in Australia) or indirect comparisons. Naïve indirect comparisons, which do not adjust for baseline differences between drugs and their comparators, were particularly common in Australia (90.0% of indirect comparison cases).

Figure 1 depicts seven cases where RCT data were utilised as a source of comparative effectiveness in at least one of the three countries, but not consistently across all of them. The reasons for not using RCT data varied, including issues related to comparators ( n = 2, England), switching ( n = 1, England), current practices ( n = 1, England), data quality ( n = 2, England and Canada), unavailability of RCT data during the appraisal ( n = 1, Canada), and cases where no appraisal was conducted. It is worth noting that NICE tended to apply stricter criteria to ensure RCT data were representative of current practices, particularly in terms of comparators, while CADTH placed greater emphasis on the availability of RCT data when selecting a comparator. Interestingly, no consistent pattern emerged in the timing or sequence of appraisal determinations among these countries.

Regarding the primary cost-effectiveness evidence, a stark contrast was observed between South Korea and the other three countries. Specifically, in South Korea, economic evidence for these drugs relied predominantly on the list prices of reference countries, as the requirement for submitting CEA data was waived. On the contrary, in the other countries, all the cases that were appraised were based on CEA data including three cases with cost-minimisation analysis.

Evidence uncertainty addressed in the appraisal of high-priced drugs

The extent to which uncertainty was addressed varied significantly across countries (Table 3 ). South Korea had the lowest rate of explicitly identifying uncertainty issues (20.8%), compared to higher rates in other countries: 73.7% in Australia and 100% in Canada. Among the other three countries, the primary focus was on efficacy-related concerns, with rates ranging from 63.2% in Australia to 95.0% in Canada. England also addressed other types of uncertainty, such as resource utilization, at a notable rate of 35.0%.

All countries implemented data collection efforts to address these uncertainties, with varying approaches and transparency. England had the highest rate of data collection (55.0%), followed by Australia (21.1%), Canada (20.0%), and South Korea (12.5%). In England, data collection was clearly aimed at generating evidence for reassessment and routine commissioning. For example, during the NICE appraisal for Tisagenlecleucel in Diffuse Large B-cell Lymphoma, clinical uncertainties like overall survival and the use of intravenous immunoglobulin therapy were identified. These uncertainties were addressed by requiring additional data collection through ongoing trials and registry data. Interim pricing arrangements, including simple discounts and commercial access agreements, were applied during this managed entry period, with reassessment planned in five years.

In contrast, data collection in other countries was less transparent due to limited available information. Australia and Canada primarily relied on manufacturers’ ongoing trials, observational studies, or existing registry data, but the intended use of this data was less explicit. In South Korea, outcome-linked refunds were implemented for recently introduced one-shot gene therapies, such as Tisagenlecleucel and Onasemnogene. Hospitals directly provided assessment data to HIRA for reimbursement purposes.

Discussion

This study offers useful insights into HTA recommendations and funding arrangements for high-priced drugs with limited evidence in four countries: England, Australia, Canada, and South Korea. Despite the lack of robust evidence, these countries exhibit high rates of positive recommendations. MEAs have been widely employed to facilitate the introduction of these expensive therapies, which are characterized by significant uncertainty and unmet patient needs. England, Australia, and Canada have implemented strategies that balance value assessment with uncertainty management, although differences remain in policy and methodology, particularly in the selection of preferred comparators. In contrast, South Korea’s CEA waiver policy has streamlined the value assessment process but has done so at the expense of adequately addressing the high costs and uncertainties associated with these drugs. As the number of such therapies continues to grow, enhancing data collection and fostering collaboration-both domestically and internationally-will be critical to improving value-for-money assessments and more effectively managing affordability and uncertainty.

Coverage recommendation and role of MEA for drugs in high unmet needs

Most of the high-priced drugs in this study received positive recommendations, ranging from 84.2% (94.7% including two drugs later subsidized through the Life Saving Drugs Program) in Australia, to 95.0% in England, and 100% in Canada, despite the uncertainty surrounding these drugs. This rate is significantly higher than those reported in earlier studies, though direct comparisons are challenging due to differences in study designs and sample selection [ 38 – 41 ]. For example, McCormick et al. found positive recommendation rates for orphan drugs ranging from 63.2% in Canada to 72.7% (92.7% including the Life Saving Drugs Program) in Australia [ 39 ]. A recent Canadian review also showed increasing approval trends for cancer drugs, from 80% in 2017 to 100% in 2018 [ 25 ]. As this study also confirms, the acceptability of uncertainty could have increased in high-income countries in recent years, with a growing pressure for timely patient access to drugs with high unmet needs. An interview with representatives of HTA agencies in Europe also confirmed that orphan drugs are appraised in the context of lower quality of evidence, although the level of acceptable uncertainty still varies by country [ 26 ].

National HTA agencies have implemented various pricing strategies to manage uncertainties. In England, all drug-indication pairs with positive recommendations ( n = 19) were introduced through some form of MEA or other special considerations, such as highly specialised technology programs, which allow for higher ICERs for ultra-orphan drugs. Of these drugs, the patient access scheme (all with simple discounts) was applied to 80% of them. Additionally, around half were covered by managed access agreements, which provide time-limit coverage for data collection, along with specific pricing measures. Furthermore, three drugs (Elosulfase alfa, Asfotase alfa, and Onasemnogene) were introduced through the highly specialised technology program, with the patient access scheme and/or managed access agreements requirements. Interestingly, Elosulfase alfa and Asfotase alfa initially received negative recommendations in Australia but were later funded through the Life Saving Drugs Program [ 36 ]. In Australia, 56.3% of the drug-indication pairs that received positive recommendations were subject to financial controls, with expenditure caps being the most common (77.8%). Caps were sometimes applied to multiple drugs for the same indication, such as Niraparib and Olaparib for ovarian cancer. More recently, 25.0% of the pairs were managed through performance-based agreements, although specific details remain unclear. It is also worth noting that there could also be more MEAs in Australia, as the existence of MEAs itself is sometimes required to be confidential [ 7 ].

In Canada, all positively recommended drugs were subject to significant price reductions and potentially additional controls. These recommendations serve as a guide for pricing negotiations conducted by the pan-Canadian Pharmaceutical Alliance and public health plans. Once negotiations are finalised, the net price is typically kept confidential, with the Ontario Auditor General’s report suggesting an average discount of about 30% from the list price (more precisely, 30% of expenditures of all branded drugs as refunds) [ 42 ]. In South Korea, expenditure caps were the default control mechanism for these drugs, but more recently, additional measures such as refunds and outcome-linked refunds have been introduced to address rising costs and uncertainties associated with newly introduced therapies.

While MEAs have facilitated patient access to high-priced drugs despite significant uncertainty, the long-term benefits for all stakeholders-manufacturers, patients, payers, and society-remain unclear. To ensure MEAs deliver their intended benefits, greater transparency and consistency in their management are needed.

Comparative evidence and uncertainty

Although the same drugs were appraised in all four countries, discrepancies emerged in the supporting evidence, particularly regarding the sources of comparative effectiveness. Even among England, Australia, and Canada, notable variations existed. In England, indirect comparisons accounted for 70% of appraisal cases, serving as the primary source of comparative effectiveness. In contrast, Australia and Canada relied on both indirect comparisons and head-to-head RCT data in roughly equal proportions.

An additional analysis was conducted to explore why RCT data were excluded in some appraisals despite being utilized in at least one peer country. The primary reason was differences in attitudes toward the representativeness of RCT data. NICE applied stricter criteria to ensure that RCT data reflected current practices, particularly in comparator selection. For example, NICE often favoured indirect comparisons aligned with NHS practices, whereas Canada prioritized the control arms (typically placebo/best supportive care) used in RCTs. Interestingly, the timing of appraisals did not significantly explain these discrepancies, as no consistent patterns were observed in the sequence of appraisals across countries.

In South Korea, expert opinions and citations were commonly relied upon as sources of comparative effectiveness, with comparative data often poorly reported. This largely reflects the committee’s focus on determining eligibility for the CEA waiver policy, where prices are primarily based on the list prices of reference countries rather than robust CEA evidence. While this approach has expedited patient access, it has introduced a trade-off between timely availability and uncertainties about value for money. Furthermore, the list prices used in these appraisals often differ significantly from the actual net prices, which are typically confidential. Reference country prices may also fail to align with value-based pricing in the Korean context. For example, in England, three drugs introduced through the highly specialised technologies programme were assessed using an ICER threshold of £100,000-£300,000-far exceeding the standard range of £20,000-£30,000. By relying on reference prices, South Korea effectively assumes a willingness to pay four to ten times higher for ultra-orphan drugs-a topic yet to be studied in the Korean context.

To improve South Korea’s assessment practices for high-priced drugs with limited evidence, aligning them more closely with international approaches is necessary to better reflect local value for money. An initial value assessment could help establish acceptable local prices and identify uncertainties requiring further investigation, akin to NICE’s approach. For instance, elosulfase alfa, introduced under the UK’s highly specialised technologies programme, received a positive conditional recommendation in 2015 for treating mucopolysaccharidosis type IVA (Morquio A) under a managed access agreement. This case involved collaboration among multiple stakeholders, including NICE, NHS England, the manufacturer, a patient organization, and a contract research organization. [ 43 ]. Patients were required to attend clinic assessments three times a year, with the option to enrol in a 10-year disease registry to contribute to long-term health and quality-of-life data collection [ 44 ]. Clear exit strategies and funding arrangements were also established. In 2022, NICE updated its guidance based on new evidence and stakeholder feedback, recommending treatment with a simple discount and removing further data collection requirements [ 43 ].

Data collection, whether part of coverage with evidence development or outcome-linked payment schemes, plays a pivotal role in ensuring early access to high-priced drugs while addressing uncertainty. Facilitating efficient data collection processes is essential for the success of such initiatives. International collaboration can be particularly valuable, especially for ultra-rare conditions, though differences in clinical practices between countries must be considered. For example, CADTH recommended elosulfase alfa with specific pricing and clinical conditions, including mandatory participation in an international registry for prospective data collection [ 45 ]. Harmonizing fragmented data sources is also critical. In South Korea, data collection is dispersed across multiple platforms serving various purposes, such as academic research, international collaboration, reimbursement, and pharmacosurveillance. Greater collaboration among industry, healthcare providers, HTA agencies, and regulatory bodies to integrate these platforms could enhance efficiency and reduce administrative burdens.

Limitations

This study has several limitations that should be considered when interpreting the results. Firstly, the study relied solely on publicly available documents. While HTA agencies may consider more comprehensive information, including submissions from manufacturers, much of this information is not accessible in public documents, particularly outside the UK. Furthermore, although this study aims to provide a comprehensive overview of MEAs across jurisdictions, the availability and level of detail of information vary. For example, in Canada, final coverage decisions with pricing arrangements are the responsibility of individual provinces and territories, limiting the availability of pan-Canadian information. Similarly, the lack of initial listing appraisal documents from NICE, when replaced with updated documents, restricted the extraction of relevant information. It should also be noted that our judgments reflect our best interpretation of the available information, which may not fully capture the nuances of these systems. Despite our efforts to ensure accuracy and comprehensiveness, HTA processes are inherently complex and can be challenging to fully understand from an external perspective.

Secondly, the high proportion of positive recommendations observed in all jurisdictions may have been influenced by the specific sample of study drugs. This study focused on 24 drug-indication pairs introduced through the CEA waiver policy in South Korea. These drugs may already have been available in other countries, possibly including those in this study. However, it should be emphasized that such drugs typically receive low rates of negative recommendations. For example, in South Korea, drugs with high unmet needs but limited evidence can be introduced as long as they meet eligibility criteria. Even drugs targeting cancers or rare diseases, introduced through the usual HTA pathways involving CEAs, have achieved reimbursement rates of approximately 95% [ 46 ]. This high acceptance rate is not unique to South Korea and is also observed in other countries [ 25 ].

Finally, as this study focused on high-priced drugs with limited evidence introduced under South Korea’s CEA waiver policy, these drugs might not always be considered expensive in other countries. However, with an average per-patient annual expenditure of $50,346 in 2021 purchasing power parity and the use of external reference pricing, the definition of high-priced drugs based on Korean data is unlikely to lead to meaningful differences in the interpretation of results.

Conclusion

This study highlights the high rate of positive recommendations for high-priced orphan drugs with unmet needs by national HTA agencies in England, Australia, Canada, and South Korea, despite the uncertainties surrounding their value. The adoption of MEAs has been a prevalent strategy to address both the financial and uncertainty challenges posed by these drugs. However, the confidential nature of these agreements, particularly concerning net prices, raises concerns about transparency across countries.

The findings reveal notable differences in how HTA agencies across these countries handle uncertainties, especially between South Korea and the others. While England, Australia, and Canada have adopted more comprehensive strategies that integrate value assessment with uncertainty management, South Korea’s approach is distinct. The CEA waiver policy in South Korea has substantially simplified value assessment for these drugs but often at the cost of overlooking uncertainties related to both clinical and cost-effectiveness.

Addressing these challenges requires a careful balance between ensuring timely access to patients and managing financial risks. In this context, enhancing strategic collaboration, both nationally and internationally, is essential for improving data collection and fostering coordinated efforts to better address the uncertainty surrounding high-priced drugs.

Supplementary Information

Supplementary Material 1.

Acknowledgements

This work was supported by the National Health Insurance Service and the National Research Foundation of Korea (NRF) grant funded by the Koreangovernment (MSIT) (No.2022R1A2C1012252).

Abbreviations

Australian Dollar

Commercial Access Agreement

Canadian Agency for Drugs and Technologies in Health

Cancer Drugs Fund

Common Drug Review

Cost-Effectiveness

Cost-Effectiveness Analysis

Coverage with Evidence Development

Cost-Minimisation Analysis

Cost-Utility Analysis

External Reference Pricing

Financial-based Agreements

Health Insurance Review and Assessment Service

Highly Specialised Technology

Health Technology Assessment

Incremental Cost-Effectiveness Ratio

Korean Won

Life Saving Drugs Program

Managed Access Agreement

Managed Entry Agreement

Medical Services Advisory Committee

National Health Insurance

National Health Service

National Institute for Health and Care Excellence

Patient Access Scheme

Performance-based Agreements

Pharmaceutical Benefits Advisory Committee

Pharmaceutical Benefits Scheme

Quality-adjusted Life Year

Randomised Controlled Trials

Risk-Sharing Agreement

Spinal Muscular Atrophy

Technology Appraisal

United Kingdom

United States

Authors’ contributions

Conceptualization, writing draft, writing review/editing (JH); conceptualization, writing review/editing, supervision (EB); data collection, review/editing (JL); data collection, review/editing (SC).

Funding

This work was supported by the National Health Insurance Service and the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. 2022R1A2C1012252).

Data availability

The data that support the findings of this study are available within the article.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

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Associated Data

Supplementary Materials

Supplementary Material 1.

Data Availability Statement

The data that support the findings of this study are available within the article.