Factors Associated with the Pricing and Reimbursement System of Orphan Drugs in South Korea

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Therefore, this study identified the factors associated with the pricing and reimbursement system of orphan drugs in South Korea. Methods The study screened a total of 66 orphan drugs out of the whole set of newly reimbursed drugs from 2012 to 2022. The analyses presented the characteristics of the orphan drugs and accounted for correlations between treatment cost and other seemingly related variables. Formal multivariate regression analyses pointed out associated factors in multivariate settings. Results Annual treatment cost per patient displayed a weakly negative correlation with the number of patients. Meanwhile, treatment cost exhibited a strongly positive correlation with the average of adjusted prices in seven advanced countries, reaching an adjusted R-squared value of 0.99. Treatment cost also showed a positive correlation with budget impact. Conclusions The pricing of orphan drugs in South Korea is predominantly influenced by external reference pricing. Drugs targeting smaller patient populations tend to be priced higher. Thus, the study highlights the interplay between drug pricing and external reference prices, drug characteristics, and pricing and reimbursement pathways. The findings can guide policymakers, pharmaceutical companies, and health care providers in their efforts to balance patient accessibility with orphan drug development and the financial sustainability of public health insurance. Orphan Drug Rare Diseases Pricing Reimbursement Budget Impact External Reference Pricing Figures Figure 1 Figure 2 Figure 3 Background With the advancement of medical and diagnostic technologies, as many as around 6,000 to 10,000 rare diseases have been identified, and the number of patients diagnosed with rare diseases has been on the rise [1-3]. Of these rare diseases, a significant proportion is chronic, progressive, debilitating, life-threatening, and/or fatal. As such, unmet medical needs with respect to rare diseases have sparked the initialization of strategic investments in these therapeutic areas [2, 4, 5]. However, rare diseases tend to have extremely low prevalence, with some occurring in a mere 1–5 per 1,000,000 people [1]. The poor prospect of commercial success, given the smaller-sized patients pool, has worked against the strategic business planning of profit-oriented pharmaceutical companies [6]. However, patients with rare diseases collectively account for 4% to 8% of the global population [1, 3]. Moreover, disease impact reverberates throughout the lives and livelihoods of patients and their families. As many as 50% of the affected are children, 30% of whom will die before they reach the age of 5 years [1, 6-8]. After the US introduced the Orphan Drug Act in 1983, other developed countries, including the EU and Japan, have followed suit. Relevant initiatives have included the designation of orphan drugs (ODs), approval of specialized marketing and post-marketing monitoring, and a raft of financial incentive programs particularly earmarked for rare diseases. Presently, over half of all countries provide subsidies for the research and development (R&D) of ODs [6, 7, 9, 10]. Moreover, subsequent market interest has led to the filing of as many as 5,099 OD applications in the United States (US); as of 2019, 724 of their pipelines (14%) have successfully reached the final approval stage [11]. In other words, the incentive legislation for orphan drugs has effectively contributed to the development of orphan drugs, thereby addressing the unmet needs of patients with rare diseases [12-14]. The sheer scale of R&D investment that has poured into the OD pipelines has naturally translated into the exorbitant pricing of such drugs, in turn limiting patient access. As such, the price setting of ODs is intertwined with the issues of patient accessibility and commercial viability for pharmaceutical companies. Despite the intervention of state-led initiatives, a wide range of discrepancies persist in terms of drug accessibility, with a large bulk of approved ODs remaining uninsured and stuck in reimbursement negotiation processes. Only around 65% of ODs approved in the EU are publicly insured as of 2018; in South Korea, the proportion is at 56%, as of 2019 [15, 16]. Reimbursement approvals are directly linked to patient accessibility—ODs would not be financially feasible options to most patients without reimbursements [15]. However, pricing and reimbursement (P&R) decisions require much caution as the number of ODs entering markets continues to arise and budgetary burdens begin to weigh down [17-20]. The pricing levels of ODs directly translate to pharmaceutical companies’ return on investment and, ultimately, long-term financial viability [21-24]. Therefore, the pricing of ODs bear great importance to all three parties involved—patients, pharmaceutical companies, and policy makers. Many countries have no specialized P&R pathways that apply only to ODs, opting instead for flexibilities and exceptions in their pricing systems, such as the use of conditional incremental cost-effectiveness ratio (ICER) threshold, weighted quality-adjusted life year (QALY), pharmaco-economic evaluation (PE) waivers, and risk-sharing agreements (RSAs) [6, 25]. Some countries have specialized funds that are earmarked for expensive medicines for fatal and rare diseases [6, 25]. To consider the incorporation of methods for assessing societal values and preferences within health technology assessments for ODs, P&R models such as multi-criteria decision analysis, proportional time trade-off, and discrete choice experiments are also examined [26, 27]. In this study, we attempted to determine the factors associated with the pricing of ODs in South Korea, with the goal of elucidating the workings and determinants of OD pricing in the country. P&R Pathways for Orphan Drugs in South Korea Four P&R pathways apply to newly approved ODs in South Korea: essential ODs, PE waived ODs, weighted average price (WAP) ODs, and PE ODs. For serious and life-threatening rare diseases, RSAs can be applied (Supplementary Figure 1) [28]. Essential and PE-waived ODs should meet a set of prescribed criteria and can be listed based on the adjusted pricing of advanced 7 countries (A7 countries: the US, the United Kingdom (UK), Germany, France, Italy, Switzerland, and Japan) without proving cost-effectiveness (Supplementary Table 1) [29]. The pricing of WAP ODs is computed based on the WAP of alternatives. PE ODs can be listed up to premium prices, with support by PE studies. External Reference Pricing for New Drugs in South Korea External reference pricing (ERP) refers to the average of adjusted A7 prices; the listing prices of newly approved drugs should not exceed the average levels. Especially for PE-waived new drugs, the lowest value of adjusted A7 prices should be used as the reference price. Adjusted prices start from ex-factory rates, upon which exchange rates, value added tax, and distribution margins are applied and added [30]. Materials and Methods Data Sources We screened a total of 66 ODs out of the whole set of newly reimbursed drugs from 2012 to 2022 from the official website of the Health Insurance Review and Assessment Service (HIRA), an agency under the Ministry of Health and Welfare of South Korea (Figure 1) [31]. The respective data on each variable were obtained from the Drug Reimbursement and Evaluation committee reports of the HIRA [32]. Our calculation of A7 adjusted prices was based on the drug pricing websites of A7 countries: Redbook Index, the US; Monthly Index of Medical Specialities, the UK; Rote Liste, Germany; Vidal, France; L'Informatore Farmaceutico, Italy; Arzneimittel Kompendium, Switzerland; and Hokenyaku Jiten (Yakugyo Kenkyukai), Japan. In line with previous research, we used annualized treatment costs to standardize OD prices using the information found in the summary of product characteristics and Korean National Health Insurance System reimbursement conditions [33, 34]. If the recommended dosage exceeds one, we used the annualized price for multiple shots; if the recommended dosage is only one for a full year, we used the price for single administration. Analysis Methods We used descriptive analyses to present the characteristics of the ODs. We applied Fisher’s exact test on the differences of RSA assignment patterns between oncology and non-oncology drugs. We broke down the annual treatment cost per patient, our dependent variable, by P&R pathway, RSA assignment, and anatomical therapeutic chemical (ATC) classification. We then looked into correlations between treatment cost and other related variables. We also conducted formal multivariate regression analyses to point out associated factors in multivariate settings. We used R version 4.3.1 to carry out statistical analyses. Prior to conducting the analyses, we found that both distributions of annual treatment cost per patient in South Korea—our variable of interest—and the corresponding A7 adjusted average prices—one of our explanatory variables—displayed highly skewed patterns to the left, with few extremely highly priced ones set apart as outliers (Supplementary Figure 2). Hence, we used log-transformed versions of both variables to make them exhibit a normalized distribution in our regressions. Results Descriptive Analyses Table 1 presents a summary of the results of the descriptive analyses. Among the distinctive characteristics, we found that ODs typically received a PE waiver, as found in 26 of the 66 ODs (39%), or WAP, noted in 21 ODs (32%). Less than a third (19, 29%) passed through PE. ODs could be roughly evenly classified into oncology (32 of 66) and non-oncology indications (34 of 66). The results of Fisher’s exact test showed that all differences were significant, except for the PE-waived case (Table 2). PE-waived ODs were the mostly likely to receive RSA assignment, compared with other pathways, regardless of oncology indication. None of non-oncology drugs that passed through WAP was RSA assigned. Table 1. Summary of Descriptive Analyses Results Variables (N = 66) Statistics Continuous Variables Annual treatment cost per patient (USD) 97,348.5 (± 216,180.4) Average of A7 adjusted prices (USD) 1,288.8 (± 2,553.3) Number of patients 519.4 (± 1116.8) Budget impact/year (USD) 6,722,323.8 (± 9,007,838.3) Number of listed countries among advanced 7 countries 5.2 (± 1.5) Categorical variables Oncology (N) Yes 32 (48.5%) No 34 (51.5%) P&R pathway (N) WAP Yes 21 (31.8%) No 45 (68.2%) PE Yes 19 (28.8%) No 47 (71.2%) PE Waiver Yes 26 (39.4%) No 40 (60.6%) RSA (N) Yes 36 (54.5%) No 30 (45.5%) ATC (N) classification A (Alimentary tract and metabolism) 8 (12.1%) B (Blood and blood forming organs) 5 (7.6%) C (Cardiovascular system) 1 (1.5%) J (General anti-infectives systemic) 5 (7.6%) L (Antineoplastic and immunomodulating agents) 42 (63.6%) M (Musculoskeletal system) 2 (3.0%) N (Nervous system) 2 (3.0%) V (Various) 1 (1.5%) Note: The descriptive statistics tabulate means and standard deviations for continuous variables and frequencies and percentages for categorical variables. Advanced 7 countries: The United States, The United Kingdom, Germany, France, Italy, Switzerland, and Japan; P&R: Pricing & Reimbursement; WAP: Weighted Average Price; PE: Pharmaco-economic Evaluation; RSA: Risk-Sharing Agreement; ATC: Anatomical Therapeutic Chemical Table 2. Breakdown of Orphan Drugs by Pricing and Reimbursement Pathway, Oncology Indication, and Risk-Sharing Agreement Assignment Note: Fisher’s exact test was used to test the differences in proportions when the null claim was that the proportions were the same. P&R: Pricing & Reimbursement; WAP: Weighted Average Price; PE: Pharmaco-economic Evaluation; RSA: Risk-Sharing Agreement On average, the PE-waived ODs tended to have a much higher average treatment cost, at USD 178,006—almost double the average of all ODs at USD 97,349 and quadruple the average of the not-PE-waived drugs. This variation may be attributed to the extreme outlier cases mostly in the PE waiver pathway (Table 3, Figure 2a). In the same way, the RSA-assigned drugs had higher average treatment costs compared with the not-RSA-assigned cases; the median gap tended to be much smaller (Table 3, Figure 2b). Meanwhile, other drugs that passed through either PE or WAP had lower averages compared with non-PE and non-WAP cases. A breakdown by ATC classification indicated that a majority of ODs (42 of 66, 64%) fell under the code L, representing antineoplastic and immunomodulating agents. The average cost of L-coded ODs, USD 49,151, was almost half that of the entire dataset, USD 97,348, but its median was slightly higher than the median of the entire set (Table 3, Figure 2c). The mean and median of ODs classified as musculoskeletal system (M), which had only two observations, were ten and three times higher, respectively, than those of the entire dataset. Table 3. Average annual treatment cost per patient by pricing and reimbursement pathway and anatomical therapeutic chemical classification Variables Mean (STD) Median Range (Min, Max) P&R pathway WAP N (N = 45, 68%) 117,586 (252,725) 42,139 (1,815, 1,531,474) Y (N = 21, 32%) 53,982 (92,064) 11,333 (34, 315,153) PE N (N = 47, 71%) 122,591 (250,808) 40,026 (34, 1,531,474) Y (N = 19, 29%) 34,905 (47,184) 23,598 (4,714, 222,288) PE Waiver N (N = 40, 61%) 44,921 (73,940) 21,619 (34, 315,153) Y (N = 26, 39%) 178,006 (319,086) 58,987 (1,815, 1,531,474) RSA N (N = 30, 45%) 47,353 (78,369) 17,551 (34, 315,153) Y (N = 36, 55%) 139,011 (278,882) 43,220 (1,667, 1,531,474) ATC classification Alimentary Tract and Metabolism (A) (N = 8) 245,916 (198,762) 221,456 (6,799, 604,187) Blood and Blood Forming Organs (B) (N = 5) 73,186 (90,186) 21,596 (11,243, 222,288) Cardiovascular System (C) (N = 1) 4,714 4,714 N.A. Anti-Infectives for Systemic Use (J) (N = 5) 13,230 (8,310) 10,238 (4,161, 23,254) Antineoplastic and Immunomodulating Agents (L) (N = 42) 49,151 (77,622) 30,490 (1,667, 455,041) Musculoskeletal System (M) (N = 2) 957,326 (811,967) 957,326 (383,179, 1,531,474) Nervous System (N) (N = 2) 20,030 (28,279) 20,030 (34, 40,026) Various (V) (N = 1) 1,815 1,815 N.A. Total (N = 66) 97,349 (216,180) 29,066 (34, 1,531,474) Note: The unit is in United States dollar (exchange = KRW 1,294/USD 1) P&R: Pricing & Reimbursement; WAP: Weighted Average Price; PE: Pharmaco-economic Evaluation; RSA: Risk-Sharing Agreement; ATC: anatomical therapeutic chemical [Table 3 here] Regression Analysis Before conducting regression analyses, we drew scatterplots for the average annual treatment cost per patient in South Korea, which is our dependent variable of interest, and three seemingly associated variables: number of patients, average of A7 adjusted prices, and budget impact (Figure 3). The annual treatment cost per patient showed a weakly negative correlation with the number of patients, a strongly positive correlation with the average of adjusted A7 prices (reaching an adjusted R -squared value of 0.99), and a positive correlation with budget impact. The scatterplots of log -transformed variables are presented in Supplementary Figure 3. Regarding the regression analysis, we set the log-transformed annual treatment cost per patient as our dependent variable and regressed it on dummy variables for oncology indication, ATC classification, P&R pathway, and RSA assignment; and continuous variables for number of patients, budget impact, number of listed countries among A7, and log-transformed average of adjusted prices in A7 countries (Table 4). To avoid multicollinearity, we checked the variance inflation factor scores. For both the regression equations of a full specification and a model without the ATC classification dummy variables, we noted that both F-statistics and adjusted R-squared values displayed fairly good signs of model fitness. [Table 4 here] Regarding the significance of individual variables, both regression equations showed that the number of patients was negatively associated with the log-transformed average treatment cost. In other words, the log of the average treatment cost could be expected to decrease by 0.005%, -0.005%=(100*(β_j ) ̂)%=(100*-0.00005)%, for the full specification and by 0.006% for the model without the ATC classification, in response to each additional patient increase. For both regression models, a 1% change in log-transformed adjusted average prices in A7 countries was associated with a β_j% change in log-transformed average treatment cost. As such, a 1% change in log(average of A7 adjusted prices) was estimated to correspond to a 1.035% increase in log(average treatment cost) for the full model and a 1.068% increase for the partial model. In the full model with a higher adjusted-R value and F-statistic, a classification as an oncology drug was associated with a -14.8% change in log(average treatment cost) compared with non-oncology cases. B- and N-coded drugs (for Blood and Blood Forming Organs and Nervous System, respectively) in the ATC classification were associated with changes of -22.4% and -69.5% in log(average treatment cost), respectively. Meanwhile, RSA-assigned drugs were associated with a 15.8% change. Both scatterplots and regression results indicated an almost one-to-one correspondence between average treatment cost in South Korea and adjusted average prices in A7 countries, indicating that the OD pricing in South Korea was highly influenced by the changes in adjusted average prices in A7 countries. The intrinsic characteristics of drugs, such as oncology indication and ATC classification, and RSA assignment status also wielded much influence. Lastly, the number of patients made a small degree of difference. Meanwhile, differences in P&R pathways and budget impact did not incur changes in average treatment cost, contrary to our expectations. Therefore, the drug characteristics that qualified ODs to certain P&R pathways and other external factors collectively characterized the pricing of ODs. Notably, the pricing of ODs in South Korea did not move in tandem over different P&R categories. The P&R pathway dummy variables collectively contributed to the overall model fitness with other explanatory variables. Meanwhile, the strong statistical association with adjusted average prices in A7 countries indicated that reference prices had the greatest impact on the pricing of ODs in South Korea. Discussion The P&R pathways have been widely regarded as the most important factor determining patients’ access to ODs [ 6 ]. Given that ODs are used by only a small fraction of the whole population, most of them are priced at an astronomical level to compensate for their R&D expenditure [ 12 ]. Therefore, patients who need ODs face difficulties in affording such prices without the help of public reimbursement [ 15 ]. From the side of biopharmaceutical companies, having their drugs listed in the reimbursement system encourages consumption, which can help drug companies recoup their hefty investment expenses in a financially viable way over the long term. Otherwise, even companies with pipelines whose safety and efficacy have passed through formal evaluation processes can go bankrupt if cash flow shortfalls occur [ 15 , 16 , 35 ]. As more ODs enter the market, P&R decisions become a major budgetary issue that policy makers have to contend with. In South Korea, the expenditure share of ODs out of the total pharmaceutical spending nationwide accounts for a mere 1%, below the 3% level of most European countries and 5% or 9% level in some countries, such as the US or Bulgaria, it can reach up to 5% or as high as 9% [ 36 , 37 ]. A study conducted in China found that the financial impact of high-cost ODs on both society and payers is relatively limited. Therefore, it was recommended that health policymakers choose suitable reimbursement strategies that align with financial feasibility [ 38 ]. Ultimately, decisions boil down to a moral dilemma between utilitarianism—maximizing outcomes with finite health care resources—and non-abandonment, which can be seen at favoritism toward those in dire needs [ 10 , 39 – 41 ]. The annual treatment costs per patient of existing ODs range between USD 1,300 and 500,000, with the average cost per patient lying between USD 32,000 and 35,000 [ 42 , 43 ]. As one of the notable cases, onasemnogene abeparvovec (Zolgensma ®) for the indication of spinal muscular atrophy can cost up to USD 2.1 million in the US and USD 1.5 million in South Korea per patient for a single administration. Therefore, even when treatment options are available, patients’ access to those therapies is not guaranteed because of monumental financial barriers [ 32 , 43 ]. Meanwhile, the return on investment of ODs, at 8.4%, far exceeds that of non-orphan drugs, 2.3%—a fact that stokes suspicion that profit-oriented corporations tap patients’ willingness to pay in the absence of alternative treatments [ 21 , 23 , 44 ]. In 2008, a total of 43 blockbuster drugs, or drugs with sales exceeding USD 1 billion, had orphan designations [ 21 ]. Given that most advanced countries implement variants of the ERP system, once-determined pricing inevitably spills over to neighboring countries and, thus, prices worldwide are aligned in some sense. Accordingly, pharmaceutical companies exploit the situation by delaying new drug launches in countries where they are highly likely to be compelled to list low prices and withdrawing marketing approvals upon unsatisfactory negotiation results in the P&R review [ 28 , 35 , 39 ]. In terms of regulatory harmonization, South Korea is placed ahead of the US, the EU, and the UK, but in terms of flexibility, it is placed behind China [ 45 ]. South Korean authorities have introduced layers of the aforementioned pathways in an attempt to accommodate the accessibility of patients in dire needs. With a variety of such systems in place, our study attempted to characterize the impactful factors associated with OD pricing patterns. Our study indicated that differences in P&R pathways and total budget impact did not significantly affect OD pricing; these displayed a strongly positive correlation with adjusted A7 prices. Instead, the intrinsic characteristics of drugs, such as oncology indication, ATC classification, and RSA assignment status, played more substantial roles in determining prices. This can be interpretated as evidence that the Korean P&R system for ODs is designed and maintained in a fair and effective manner. OD pricing decisions are based solely on objective factors, such as product characteristics and adjusted A7 prices, indicating that the system operates strictly within established policies, free from bias by other factors. The lack of influence of budget impacts on the annual treatment cost per patient suggests that the government is pursuing utilitarianism in OD pricing, to ensure the financial stability of the overall insurance system. Notably, ODs that passed through PE waiver with RSA tended to have higher average annual treatment costs, compared with those that passed the WAP or PE pathways. All ODs included in our study were developed by foreign companies and launched first in other countries before entering the South Korean market. The Korean government’s implementation of the ERP system has resulted in an almost one-to-one correspondence between adjusted A7 prices and Korean market OD prices, leaving only a limited scope for other determinants to influence pricing. Our study had a number of limitations. First, in South Korea, RSAs, which require mandatory pay-back if sales exceed pre-specified thresholds, represent one of the most financially supportive mechanisms toward payers. As such, the listed and adjusted prices may have unrealized gaps and may not match the actual prices paid by patients. In our study, as much as 54.5% of ODs included (i.e., 36 drugs) were classified as RSAs. Second, we calculated the annual treatment cost per patient based on the dosage regimen approved by Korean Ministry of Food and Drug Safety. However, in real-world cases, treatment cost is influenced by physicians’ clinical guidelines or reimbursement criteria insurance standards. As such, the actual prices may differ from the prices that we calculated. Conclusions Our study delineated the factors with actual influences on OD pricing, highlighting the interplay between OD pricing and external reference prices, drug characteristics, and number of patients. In light of these results, we recommend the adoption of a flexible approach to OD pricing decisions to ensure that patients with ultra-rare diseases are not marginalized in terms of treatment access. Our findings can guide policymakers, pharmaceutical companies, and health care providers in their efforts to balance patient accessibility with orphan drug development and the financial sustainability of public health insurance. Abbreviations OD: orphan drug R&D: research and development P&R: pricing and reimbursement ATC: anatomical therapeutic chemical PE: pharmaco-economic evaluation WAP: weighted average price RSA: risk-sharing agreements ERP: external reference pricing HIRA: Health Insurance Review and Assessment Service Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Availability of data and materials The datasets analyzed in this study are available from the corresponding author upon reasonable request. Competing interests The authors declare that they have no competing interests. Funding Not applicable. Author’s Contributions SHL and SKL contributed to the study design, data collection, statistical analysis, manuscript development, and review. JHL and JSB supervised the entirety of the study, from study design, data collection and analysis, and manuscript editing to manuscript submission. 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Orphanet Journal of Rare Diseases 2021; 16:1–12. Vásquez P, Hall L, Merlo G. Societal Preferences in Health Technology Assessments for Rare Diseases and Orphan Drugs: A Systematic Literature Review of New Analytic Approaches. Value in Health Regional Issues 2024; 44:101026. Lee JH. Pricing and Reimbursement Pathways of New Orphan Drugs in South Korea: A Longitudinal Comparison. Healthcare (Basel) 2021; 9. doi: 10.3390/healthcare9030296 . Bang JS, Lee JH. The national drug formulary listing process for orphan drugs in South Korea: narrative review focused on pricing and reimbursement pathways. Expert Opinion on Orphan Drugs 2021; 9:105–112. Kim S, Kim J, Cho H, Lee K, Ryu C, Lee JH. Trends in the pricing and reimbursement of new anticancer drugs in South Korea: an analysis of listed anticancer drugs during the past three years. Expert Review of Pharmacoeconomics & Outcomes Research 2021; 21:479–488. HIRA. Reimbursement History Information In: [ https://www.hira.or.kr/ra/medi/getHistoryList.do?pgmid=HIRAA030035020000] . Accessed Oct 02 2024. HIRA. Drug Reimbursement and Evaluation Committee In: [ https://www.hira.or.kr/bbsDummy.do?pgmid=HIRAA030014040000] . Accessed Oct 02 2024. Jommi C, Listorti E, Villa F, Ghislandi S, Genazzani A, Cangini A, Trotta F. Variables affecting pricing of orphan drugs: the Italian case. Orphanet Journal of Rare Diseases 2021; 16:1–10. Villa F, Di Filippo A, Pierantozzi A, Genazzani A, Addis A, Trifirò G, Cangini A, Tafuri G, Settesoldi D, Trotta F. Orphan drug prices and epidemiology of rare diseases: a cross-sectional study in italy in the years 2014–2019. Frontiers in Medicine 2022; 9:820757. Rollet P, Lemoine A, Dunoyer M. Sustainable rare diseases business and drug access: no time for misconceptions. Orphanet journal of rare diseases 2013; 8:1–9. Gombocz M, Vogler S. Public spending on orphan medicines: a review of the literature. Journal of Pharmaceutical Policy and Practice 2020; 13:66. Teagarden JR, Unger TF, Hirsch G. Access and availability of orphan drugs in the United States: advances or cruel hoaxes? Expert Opinion on Orphan Drugs 2014; 2:1147–1150. Zhang X, Zhou T, Zhou J, Zhang D, Yang Y, Pan J. Budget impact analysis of high-priced orphan medicinal products intended for the treatment of rare diseases in China: evidence from a densely populated metropolis of Chengdu. BMC Health Serv Res 2024; 24:1123. doi: 10.1186/s12913-024-11632-6 . Kanavos P, Fontrier A-M, Gill J, Efthymiadou O. Does external reference pricing deliver what it promises? Evidence on its impact at national level. The European Journal of Health Economics 2020; 21:129–151. Onakpoya IJ, Spencer EA, Thompson MJ, Heneghan CJ. Effectiveness, safety and costs of orphan drugs: an evidence-based review. BMJ open 2015; 5:e007199. Zimmermann BM, Eichinger J, Baumgartner MR. A systematic review of moral reasons on orphan drug reimbursement. Orphanet J Rare Dis 2021; 16:292. doi: 10.1186/s13023-021-01925-y . Institute I: Orphan Drugs in thr United States: Rare disease innovation and coast trends through 2019. 2020. Schey C, Milanova T, Hutchings A. Estimating the budget impact of orphan medicines in Europe: 2010–2020. Orphanet journal of rare diseases 2011; 6:1–10. Rzakhanov Z. Regulatory policy, value of knowledge assets and innovation strategy: The case of the Orphan Drug Act. Research Policy 2008; 37:673–689. Institute I: Global Trends in R&D 2024: Activity, productivity, and enablers. 2024. Table Table 4 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files SupplymentaryMeterial.docx Table4.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5336091","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":371499613,"identity":"522db3ef-8b48-4edf-946f-d90b2c147cf5","order_by":0,"name":"Se Hee Lee","email":"","orcid":"","institution":"Sookmyung Women’s University","correspondingAuthor":false,"prefix":"","firstName":"Se","middleName":"Hee","lastName":"Lee","suffix":""},{"id":371499614,"identity":"efbc8e66-9ed9-4b3d-830b-d12b4488c446","order_by":1,"name":"Sung Kyung Lee","email":"","orcid":"","institution":"Korea Institute for Industrial Economics and Trade","correspondingAuthor":false,"prefix":"","firstName":"Sung","middleName":"Kyung","lastName":"Lee","suffix":""},{"id":371499615,"identity":"ed413cc0-7443-4fa1-b8a8-f0953d2485ab","order_by":2,"name":"Joon Seok Bang","email":"","orcid":"","institution":"Sookmyung Women’s University","correspondingAuthor":false,"prefix":"","firstName":"Joon","middleName":"Seok","lastName":"Bang","suffix":""},{"id":371499616,"identity":"dc21a20a-70e8-407c-9d18-35e9a86c6994","order_by":3,"name":"Jong Hyuk Lee","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwklEQVRIiWNgGAWjYLACyQYbGDOBaC1ppGphbDhMghb+/uMPP1juOC/PPyOB8cMPhrR8glokbuQYS0ieuW0440YCs2QPQ45lA0E9N3gYJCTbbicw3EhgkGZgqDAgqEP+/PHHPyTbziXIA235TZQWgwMJZkBbDiQY3EhgA9qSQ1iL4Y0cMwvJtmTDjWcetln2GKQR1iIHdNhtyTY7ebnjyYdv/KhIJqwFBJglwBRjA9CdRGkAqv1ApMJRMApGwSgYoQAANEU5iwWiulMAAAAASUVORK5CYII=","orcid":"","institution":"Chung-Ang University","correspondingAuthor":true,"prefix":"","firstName":"Jong","middleName":"Hyuk","lastName":"Lee","suffix":""}],"badges":[],"createdAt":"2024-10-26 07:23:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5336091/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5336091/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":69420752,"identity":"9a37482f-3f68-49de-b423-7c663a8cf125","added_by":"auto","created_at":"2024-11-20 07:45:14","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":223406,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart for data screening. Note: HIRA: health insurance review and assessment service; OD: orphan drug; MA: marketing authorization\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-5336091/v1/a41c3e7456f9f024d56e94c6.jpeg"},{"id":69421294,"identity":"fbd707c6-fa45-4281-bbeb-ab6cbb475944","added_by":"auto","created_at":"2024-11-20 07:53:14","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":350275,"visible":true,"origin":"","legend":"\u003cp\u003eBox plots of annual treatment cost per patient by pricing and reimbursement pathway, risk-sharing agreement, and anatomical therapeutic chemical classification system. (a) Annual treatments per patient using the pricing and reimbursement pathway, (b) Annual treatment per patient with risk-sharing agreement, (c) Annual treatment per patient according to anatomical therapeutic chemical classification. Note: The x-axis represents the annual treatment cost per patient in United States dollar (exchange = Korea Won 1,294 /USD 1).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5336091/v1/98bcba0485a0bbb50cac3e67.png"},{"id":69420753,"identity":"117c9f47-a611-4766-8107-0d6a0d510e8f","added_by":"auto","created_at":"2024-11-20 07:45:14","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":292301,"visible":true,"origin":"","legend":"\u003cp\u003eScatterplots of annual treatment cost per patient against major variables (1. Number of patients, 2. Average \u0026nbsp;adjusted prices of advanced 7 countries, and 3. Budget impact)\u003c/p\u003e","description":"","filename":"floatimage6.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-5336091/v1/af5b2f155e55caef2922d4b2.jpeg"},{"id":74540798,"identity":"87418762-9784-4b7c-bfcb-88d465b6b8f9","added_by":"auto","created_at":"2025-01-23 09:17:14","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1488970,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5336091/v1/294a8bc5-de60-4dc3-ac8d-f58449a8e26b.pdf"},{"id":69420750,"identity":"d88f0362-33a8-4c33-af64-654f04be5536","added_by":"auto","created_at":"2024-11-20 07:45:14","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":141053,"visible":true,"origin":"","legend":"","description":"","filename":"SupplymentaryMeterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-5336091/v1/1e52d9ee3bbe8cbcee6d56ae.docx"},{"id":69420749,"identity":"8f65ee3d-ba40-4309-adf5-10177523523a","added_by":"auto","created_at":"2024-11-20 07:45:14","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":33667,"visible":true,"origin":"","legend":"","description":"","filename":"Table4.docx","url":"https://assets-eu.researchsquare.com/files/rs-5336091/v1/fc28999807d502ce27ae7f59.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Factors Associated with the Pricing and Reimbursement System of Orphan Drugs in South Korea","fulltext":[{"header":"Background","content":"\u003cp\u003eWith the advancement of medical and diagnostic technologies, as many as around 6,000 to 10,000 rare diseases have been identified, and the number of patients diagnosed with rare diseases has been on the rise\u0026nbsp;[1-3]. Of these rare diseases, a significant proportion is chronic, progressive, debilitating, life-threatening, and/or fatal. As such, unmet medical needs with respect to rare diseases have sparked the initialization of strategic investments in these therapeutic areas\u0026nbsp;[2, 4, 5].\u0026nbsp;However, rare diseases tend to have extremely low prevalence, with some occurring in a\u0026nbsp;mere 1\u0026ndash;5 per\u0026nbsp;1,000,000 people\u0026nbsp;[1]. The poor prospect of commercial success, given the smaller-sized patients pool, has worked against the strategic business planning of profit-oriented pharmaceutical companies\u0026nbsp;[6]. However, patients with rare diseases collectively account for 4% to 8% of the global population\u0026nbsp;[1, 3].\u0026nbsp;Moreover, disease impact reverberates throughout the lives and livelihoods of patients and their families. As many as 50% of the affected are children, 30% of whom\u0026nbsp;will die before they reach the age of 5 years\u0026nbsp;[1, 6-8].\u003c/p\u003e\n\u003cp\u003eAfter the US introduced the Orphan Drug Act in 1983, other developed countries, including the EU and Japan, have followed suit. Relevant initiatives have included the designation of orphan drugs (ODs), approval of specialized marketing and post-marketing monitoring, and a raft of financial incentive programs particularly earmarked for rare diseases.\u0026nbsp;Presently, over half of all countries\u0026nbsp;provide subsidies for the research and development (R\u0026amp;D) of ODs\u0026nbsp;[6, 7, 9, 10].\u0026nbsp;Moreover, subsequent market interest has led to the filing of as many as 5,099 OD applications\u0026nbsp;in the United States (US); as of 2019, 724 of their pipelines (14%) have successfully reached the final approval stage\u0026nbsp;[11]. In other words, the incentive legislation for orphan drugs has effectively contributed to the development of orphan drugs, thereby addressing the unmet needs of patients with rare diseases\u0026nbsp;[12-14].\u003c/p\u003e\n\u003cp\u003eThe sheer scale of R\u0026amp;D investment that has poured into the OD pipelines has naturally translated into the exorbitant pricing of such drugs, in turn limiting patient access. As such, the price setting of ODs is intertwined with the issues of patient accessibility and commercial viability for pharmaceutical companies. Despite\u0026nbsp;the intervention of state-led initiatives, a wide range of discrepancies persist in terms of drug accessibility, with a large bulk of approved ODs remaining uninsured and stuck in reimbursement negotiation processes. Only around 65% of ODs approved in the\u0026nbsp;EU are publicly insured as of 2018; in South Korea, the proportion is at 56%,\u0026nbsp;as of 2019\u0026nbsp;[15, 16].\u003c/p\u003e\n\u003cp\u003eReimbursement approvals are directly linked to patient accessibility\u0026mdash;ODs would not be financially feasible options to most patients without reimbursements\u0026nbsp;[15]. However, pricing and reimbursement (P\u0026amp;R) decisions require much caution as the number of ODs entering markets continues to arise and budgetary burdens begin to weigh down\u0026nbsp;[17-20]. The pricing levels of ODs directly translate to pharmaceutical companies\u0026rsquo; return on investment and, ultimately, long-term financial viability\u0026nbsp;[21-24]. Therefore, the pricing of ODs bear great importance to all three parties involved\u0026mdash;patients, pharmaceutical companies, and policy makers.\u003c/p\u003e\n\u003cp\u003eMany countries have no specialized P\u0026amp;R pathways that apply only to ODs, opting instead for flexibilities and exceptions in their pricing systems,\u0026nbsp;such as the use of conditional incremental cost-effectiveness ratio (ICER) threshold, weighted quality-adjusted life year (QALY), pharmaco-economic evaluation (PE) waivers, and risk-sharing agreements (RSAs)\u0026nbsp;[6, 25]. Some countries have specialized funds that are earmarked for expensive medicines for fatal and rare diseases\u0026nbsp;[6, 25].\u0026nbsp;To consider the incorporation of methods for assessing societal values and preferences within health technology assessments\u0026nbsp;for ODs,\u0026nbsp;P\u0026amp;R models\u0026nbsp;such as multi-criteria decision analysis, proportional time trade-off, and discrete choice experiments\u0026nbsp;are also\u0026nbsp;examined\u0026nbsp;[26, 27].\u003c/p\u003e\n\u003cp\u003eIn this study, we attempted to determine the factors associated with the pricing of ODs in South Korea, with the goal of elucidating the workings and determinants of OD pricing in the country.\u003c/p\u003e\n\u003ch2\u003eP\u0026amp;R Pathways for Orphan Drugs in South Korea\u003c/h2\u003e\n\u003cp\u003eFour P\u0026amp;R pathways apply to newly approved ODs in South Korea: essential ODs, PE\u0026nbsp;waived ODs, weighted average price (WAP) ODs, and PE ODs. For serious and life-threatening rare diseases,\u0026nbsp;RSAs can be applied (Supplementary Figure 1)\u0026nbsp;[28]. Essential and PE-waived ODs should meet a set of prescribed criteria and can be listed based on the adjusted pricing of\u0026nbsp;advanced 7 countries (A7 countries: the US, the United Kingdom (UK), Germany, France, Italy, Switzerland, and Japan)\u0026nbsp;without proving cost-effectiveness (Supplementary Table 1)\u0026nbsp;[29]. The pricing of WAP ODs is computed based on the WAP of alternatives. PE ODs can be listed up to premium prices, with support by\u0026nbsp;PE\u0026nbsp;studies.\u003c/p\u003e\n\u003ch2\u003eExternal Reference Pricing for New Drugs in South Korea\u003c/h2\u003e\n\u003cp\u003eExternal reference pricing (ERP) refers to the average of adjusted A7 prices; the listing prices of newly approved drugs should not exceed the average levels. Especially for PE-waived new drugs, the lowest value of adjusted A7 prices should be used as the reference price. Adjusted prices start from ex-factory rates, upon which exchange rates, value added tax, and distribution margins are applied and added [30].\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003ch2\u003eData Sources\u003c/h2\u003e\n\u003cp\u003eWe screened a total of 66 ODs out of the whole set of newly reimbursed drugs from 2012 to 2022 from the official website of the Health Insurance Review and Assessment Service (HIRA), an agency under the Ministry of Health and Welfare of South Korea (Figure 1)\u0026nbsp;[31]. The respective data on each variable were obtained from the Drug Reimbursement and Evaluation committee reports of the HIRA\u0026nbsp;[32]. Our calculation of A7 adjusted prices was based on the drug pricing websites of A7 countries: Redbook Index, the US; Monthly Index of Medical Specialities, the UK; Rote Liste, Germany; Vidal, France; L\u0026apos;Informatore Farmaceutico, Italy; Arzneimittel Kompendium, Switzerland; and Hokenyaku Jiten (Yakugyo Kenkyukai), Japan. In line with previous research, we used annualized treatment costs to standardize OD prices using the information found in the summary of product characteristics and Korean National Health Insurance System reimbursement conditions\u0026nbsp;[33, 34].\u0026nbsp;If the recommended dosage exceeds one, we used the annualized price for multiple shots; if the recommended dosage is only one for a full year, we used the price for\u0026nbsp;single administration.\u003c/p\u003e\n\u003ch2\u003eAnalysis Methods\u003c/h2\u003e\n\u003cp\u003eWe used descriptive analyses to present the characteristics of the ODs. We applied Fisher\u0026rsquo;s\u0026nbsp;exact test\u0026nbsp;on the differences of\u0026nbsp;RSA assignment patterns between oncology and non-oncology drugs.\u0026nbsp;We broke down the annual treatment cost per patient, our dependent variable,\u0026nbsp;by P\u0026amp;R pathway, RSA assignment, and anatomical therapeutic chemical (ATC) classification. We then looked into correlations between treatment cost and other related variables. We also conducted\u0026nbsp;formal multivariate regression analyses to\u0026nbsp;point out associated factors in multivariate settings. We used R version 4.3.1 to carry out statistical analyses.\u003c/p\u003e\n\u003cp\u003ePrior to conducting the analyses, we found that both distributions of annual treatment cost per patient in South Korea\u0026mdash;our variable of interest\u0026mdash;and the corresponding A7 adjusted average prices\u0026mdash;one of our explanatory variables\u0026mdash;displayed highly skewed patterns to the left, with few extremely highly priced ones set apart as outliers (Supplementary Figure 2). Hence, we used log-transformed versions of both variables to make them exhibit a normalized distribution in our regressions.\u003c/p\u003e"},{"header":"Results","content":"\u003ch2\u003eDescriptive Analyses\u003c/h2\u003e\n\u003cp\u003eTable 1 presents a summary of the results of the\u0026nbsp;descriptive analyses. Among the distinctive characteristics, we found that ODs\u0026nbsp;typically received a PE waiver, as found in 26 of the 66 ODs (39%), or WAP, noted in 21 ODs (32%). Less than a third (19, 29%)\u0026nbsp;passed\u0026nbsp;through PE. ODs\u0026nbsp;could be roughly evenly classified into oncology (32 of 66) and non-oncology indications (34 of 66). The results of Fisher\u0026rsquo;s\u0026nbsp;exact test showed that all differences were significant, except for\u0026nbsp;the PE-waived case (Table 2). PE-waived ODs were the mostly likely to receive RSA assignment, compared with other pathways, regardless of oncology indication. None of\u0026nbsp;non-oncology drugs that passed through WAP\u0026nbsp;was RSA assigned.\u003c/p\u003e\n\u003cp\u003eTable 1. Summary of Descriptive Analyses Results\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"left\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" style=\"width: 73%;\"\u003e\n \u003cp\u003eVariables (N = 66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26%;\"\u003e\n \u003cp\u003eStatistics\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"5\" style=\"width: 13%;\"\u003e\n \u003cp\u003eContinuous Variables\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 60%;\"\u003e\n \u003cp\u003eAnnual treatment cost per patient (USD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26%;\"\u003e\n \u003cp\u003e97,348.5 (\u0026plusmn; 216,180.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" style=\"width: 60%;\"\u003e\n \u003cp\u003eAverage of A7 adjusted prices (USD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26%;\"\u003e\n \u003cp\u003e1,288.8 (\u0026plusmn; 2,553.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" style=\"width: 60%;\"\u003e\n \u003cp\u003eNumber of patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26%;\"\u003e\n \u003cp\u003e519.4 (\u0026plusmn; 1116.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" style=\"width: 60%;\"\u003e\n \u003cp\u003eBudget impact/year (USD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26%;\"\u003e\n \u003cp\u003e6,722,323.8 (\u0026plusmn; 9,007,838.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" style=\"width: 60%;\"\u003e\n \u003cp\u003eNumber of listed countries among\u0026nbsp;advanced\u0026nbsp;7\u0026nbsp;countries\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26%;\"\u003e\n \u003cp\u003e5.2 (\u0026plusmn; 1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"18\" style=\"width: 13%;\"\u003e\n \u003cp\u003eCategorical variables\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" rowspan=\"2\" style=\"width: 30%;\"\u003e\n \u003cp\u003eOncology (N)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26%;\"\u003e\n \u003cp\u003e32 (48.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26%;\"\u003e\n \u003cp\u003e34 (51.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"6\" style=\"width: 11%;\"\u003e\n \u003cp\u003eP\u0026amp;R pathway\u003c/p\u003e\n \u003cp\u003e(N)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 19%;\"\u003e\n \u003cp\u003eWAP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26%;\"\u003e\n \u003cp\u003e21 (31.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26%;\"\u003e\n \u003cp\u003e45 (68.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 19%;\"\u003e\n \u003cp\u003ePE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26%;\"\u003e\n \u003cp\u003e19 (28.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26%;\"\u003e\n \u003cp\u003e47 (71.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 19%;\"\u003e\n \u003cp\u003ePE Waiver\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26%;\"\u003e\n \u003cp\u003e26 (39.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26%;\"\u003e\n \u003cp\u003e40 (60.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" rowspan=\"2\" style=\"width: 30%;\"\u003e\n \u003cp\u003eRSA (N)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 29%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26%;\"\u003e\n \u003cp\u003e36 (54.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26%;\"\u003e\n \u003cp\u003e30 (45.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"8\" style=\"width: 11%;\"\u003e\n \u003cp\u003eATC (N)\u0026nbsp;classification\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 48%;\"\u003e\n \u003cp\u003eA (Alimentary tract and metabolism)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26%;\"\u003e\n \u003cp\u003e8 (12.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 48%;\"\u003e\n \u003cp\u003eB (Blood and blood forming organs)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26%;\"\u003e\n \u003cp\u003e5 (7.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 48%;\"\u003e\n \u003cp\u003eC (Cardiovascular system)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26%;\"\u003e\n \u003cp\u003e1 (1.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 48%;\"\u003e\n \u003cp\u003eJ (General anti-infectives systemic)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26%;\"\u003e\n \u003cp\u003e5 (7.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 48%;\"\u003e\n \u003cp\u003eL (Antineoplastic and immunomodulating agents)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26%;\"\u003e\n \u003cp\u003e42 (63.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 48%;\"\u003e\n \u003cp\u003eM (Musculoskeletal system)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26%;\"\u003e\n \u003cp\u003e2 (3.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 48%;\"\u003e\n \u003cp\u003eN (Nervous system)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26%;\"\u003e\n \u003cp\u003e2 (3.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 48%;\"\u003e\n \u003cp\u003eV (Various)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26%;\"\u003e\n \u003cp\u003e1 (1.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eNote: The descriptive statistics tabulate means and standard deviations for continuous variables and frequencies and percentages for categorical variables.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAdvanced 7 countries: The United States, The United Kingdom, Germany, France, Italy, Switzerland, and Japan; P\u0026amp;R: Pricing \u0026amp; Reimbursement; WAP: Weighted Average Price; PE: Pharmaco-economic Evaluation; RSA: Risk-Sharing Agreement; ATC: Anatomical Therapeutic Chemical\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2. Breakdown of Orphan Drugs by Pricing and Reimbursement Pathway, Oncology Indication, and Risk-Sharing Agreement Assignment\u003c/p\u003e\n\u003cp\u003e\u003cimg src=\"data:image/png;base64,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\" width=\"640\" height=\"381\"\u003e\u003c/p\u003e\n\u003cp\u003eNote: Fisher\u0026rsquo;s\u0026nbsp;exact test was used to test the differences in proportions when the null\u0026nbsp;claim was that the proportions were the same.\u003c/p\u003e\n\u003cp\u003eP\u0026amp;R: Pricing \u0026amp; Reimbursement; WAP: Weighted Average Price; PE: Pharmaco-economic Evaluation; RSA: Risk-Sharing Agreement\u003c/p\u003e\n\u003cp\u003eOn average, the PE-waived ODs tended\u0026nbsp;to have a much higher average treatment cost, at USD 178,006\u0026mdash;almost double the average of all ODs at USD 97,349 and quadruple the average of the not-PE-waived drugs. This variation may be attributed to the extreme outlier cases mostly in the PE waiver pathway (Table 3, Figure 2a). In the same way, the RSA-assigned drugs had higher average treatment costs compared with the not-RSA-assigned cases; the median gap tended to be much smaller (Table 3, Figure 2b). Meanwhile, other drugs that passed through either PE or WAP had lower averages compared with non-PE and non-WAP cases.\u003c/p\u003e\n\u003cp\u003eA breakdown by ATC classification indicated that a majority of ODs (42 of 66, 64%) fell under the code L, representing antineoplastic and immunomodulating agents. The average cost of L-coded ODs, USD 49,151, was almost half that of the entire dataset, USD 97,348, but its median was slightly higher than the median of the entire set (Table 3, Figure 2c). The mean and median of ODs classified as musculoskeletal system (M), which had only two observations, were ten and three times higher, respectively, than those of the entire dataset.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 3.\u0026nbsp;Average annual treatment cost per patient by pricing and reimbursement pathway and anatomical\u0026nbsp;therapeutic\u0026nbsp;chemical\u0026nbsp;classification\u0026nbsp;\u003c/p\u003e\n\u003cdiv align=\"center\"\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" style=\"width: 55%;\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13%;\"\u003e\n \u003cp\u003eMean (STD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12%;\"\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18%;\"\u003e\n \u003cp\u003eRange (Min, Max)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"6\" style=\"width: 11%;\"\u003e\n \u003cp\u003eP\u0026amp;R pathway\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 13%;\"\u003e\n \u003cp\u003eWAP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30%;\"\u003e\n \u003cp\u003eN (N = 45, 68%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13%;\"\u003e\n \u003cp\u003e117,586\u003c/p\u003e\n \u003cp\u003e(252,725)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12%;\"\u003e\n \u003cp\u003e42,139\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18%;\"\u003e\n \u003cp\u003e(1,815, 1,531,474)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 30%;\"\u003e\n \u003cp\u003eY (N = 21, 32%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13%;\"\u003e\n \u003cp\u003e53,982\u003c/p\u003e\n \u003cp\u003e(92,064)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12%;\"\u003e\n \u003cp\u003e11,333\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18%;\"\u003e\n \u003cp\u003e(34, 315,153)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 13%;\"\u003e\n \u003cp\u003ePE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30%;\"\u003e\n \u003cp\u003eN (N = 47, 71%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13%;\"\u003e\n \u003cp\u003e122,591\u003c/p\u003e\n \u003cp\u003e(250,808)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12%;\"\u003e\n \u003cp\u003e40,026\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18%;\"\u003e\n \u003cp\u003e(34, 1,531,474)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 30%;\"\u003e\n \u003cp\u003eY (N = 19, 29%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13%;\"\u003e\n \u003cp\u003e34,905\u003c/p\u003e\n \u003cp\u003e(47,184)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12%;\"\u003e\n \u003cp\u003e23,598\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18%;\"\u003e\n \u003cp\u003e(4,714, 222,288)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 13%;\"\u003e\n \u003cp\u003ePE Waiver\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30%;\"\u003e\n \u003cp\u003eN (N = 40, 61%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13%;\"\u003e\n \u003cp\u003e44,921\u003c/p\u003e\n \u003cp\u003e(73,940)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12%;\"\u003e\n \u003cp\u003e21,619\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18%;\"\u003e\n \u003cp\u003e(34, 315,153)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 30%;\"\u003e\n \u003cp\u003eY (N = 26, 39%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13%;\"\u003e\n \u003cp\u003e178,006\u003c/p\u003e\n \u003cp\u003e(319,086)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12%;\"\u003e\n \u003cp\u003e58,987\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18%;\"\u003e\n \u003cp\u003e(1,815, 1,531,474)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 11%;\"\u003e\n \u003cp\u003eRSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 43%;\"\u003e\n \u003cp\u003eN (N = 30, 45%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13%;\"\u003e\n \u003cp\u003e47,353\u003cbr\u003e\u0026nbsp;(78,369)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12%;\"\u003e\n \u003cp\u003e17,551\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18%;\"\u003e\n \u003cp\u003e(34, 315,153)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 43%;\"\u003e\n \u003cp\u003eY (N = 36, 55%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13%;\"\u003e\n \u003cp\u003e139,011\u003cbr\u003e\u0026nbsp;(278,882)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12%;\"\u003e\n \u003cp\u003e43,220\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18%;\"\u003e\n \u003cp\u003e(1,667, 1,531,474)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"8\" style=\"width: 11%;\"\u003e\n \u003cp\u003eATC\u0026nbsp;classification\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 43%;\"\u003e\n \u003cp\u003eAlimentary Tract and Metabolism (A) (N = 8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13%;\"\u003e\n \u003cp\u003e245,916\u003c/p\u003e\n \u003cp\u003e(198,762)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12%;\"\u003e\n \u003cp\u003e221,456\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18%;\"\u003e\n \u003cp\u003e(6,799, 604,187)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 43%;\"\u003e\n \u003cp\u003eBlood and Blood Forming Organs (B) (N = 5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13%;\"\u003e\n \u003cp\u003e73,186\u003c/p\u003e\n \u003cp\u003e(90,186)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12%;\"\u003e\n \u003cp\u003e21,596\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18%;\"\u003e\n \u003cp\u003e(11,243, 222,288)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 43%;\"\u003e\n \u003cp\u003eCardiovascular System (C) (N = 1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13%;\"\u003e\n \u003cp\u003e4,714\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12%;\"\u003e\n \u003cp\u003e4,714\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18%;\"\u003e\n \u003cp\u003eN.A.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 43%;\"\u003e\n \u003cp\u003eAnti-Infectives for Systemic Use (J) (N = 5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13%;\"\u003e\n \u003cp\u003e13,230\u003c/p\u003e\n \u003cp\u003e(8,310)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12%;\"\u003e\n \u003cp\u003e10,238\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18%;\"\u003e\n \u003cp\u003e(4,161, 23,254)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 43%;\"\u003e\n \u003cp\u003eAntineoplastic and Immunomodulating Agents (L) (N = 42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13%;\"\u003e\n \u003cp\u003e49,151\u003c/p\u003e\n \u003cp\u003e(77,622)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12%;\"\u003e\n \u003cp\u003e30,490\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18%;\"\u003e\n \u003cp\u003e(1,667, 455,041)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 43%;\"\u003e\n \u003cp\u003eMusculoskeletal System (M) (N = 2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13%;\"\u003e\n \u003cp\u003e957,326\u003cbr\u003e\u0026nbsp;(811,967)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12%;\"\u003e\n \u003cp\u003e957,326\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18%;\"\u003e\n \u003cp\u003e(383,179, 1,531,474)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 43%;\"\u003e\n \u003cp\u003eNervous System (N) (N = 2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13%;\"\u003e\n \u003cp\u003e20,030\u003c/p\u003e\n \u003cp\u003e(28,279)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12%;\"\u003e\n \u003cp\u003e20,030\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18%;\"\u003e\n \u003cp\u003e(34, 40,026)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 43%;\"\u003e\n \u003cp\u003eVarious (V) (N = 1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13%;\"\u003e\n \u003cp\u003e1,815\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12%;\"\u003e\n \u003cp\u003e1,815\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18%;\"\u003e\n \u003cp\u003eN.A.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" style=\"width: 55%;\"\u003e\n \u003cp\u003eTotal (N = 66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13%;\"\u003e\n \u003cp\u003e97,349\u003c/p\u003e\n \u003cp\u003e(216,180)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12%;\"\u003e\n \u003cp\u003e29,066\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18%;\"\u003e\n \u003cp\u003e(34, 1,531,474)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNote: The unit\u0026nbsp;is in\u0026nbsp;United States dollar\u0026nbsp;(exchange = KRW 1,294/USD 1)\u003c/p\u003e\n\u003cp\u003eP\u0026amp;R: Pricing \u0026amp; Reimbursement; WAP: Weighted Average Price; PE: Pharmaco-economic Evaluation; RSA: Risk-Sharing Agreement; ATC: anatomical therapeutic chemical\u003c/p\u003e\n\u003cp\u003e[Table 3 here]\u003c/p\u003e\n\u003ch2\u003eRegression Analysis\u003c/h2\u003e\n\u003cp\u003eBefore conducting\u0026nbsp;regression analyses, we drew scatterplots for the average annual treatment cost per patient in South Korea, which is our dependent variable of interest, and\u0026nbsp;three seemingly associated variables: number of patients, average of A7 adjusted prices, and budget impact (Figure\u0026nbsp;3). The annual treatment cost per patient showed a weakly negative correlation with the number of patients, a strongly positive\u0026nbsp;correlation with the average of adjusted A7 prices (reaching an adjusted \u003cem\u003eR\u003c/em\u003e-squared value of 0.99), and a positive correlation with budget impact.\u0026nbsp;The scatterplots of \u003cem\u003elog\u003c/em\u003e-transformed variables are presented in Supplementary Figure\u0026nbsp;3.\u003c/p\u003e\n\u003cp\u003eRegarding the regression analysis, we set the\u0026nbsp;log-transformed annual treatment cost per patient as our dependent variable and regressed it on dummy variables for oncology indication, ATC classification, P\u0026amp;R pathway, and RSA assignment; and continuous variables for number of patients, budget impact, number of listed countries among A7, and log-transformed average of adjusted prices in A7 countries (Table 4). To avoid multicollinearity, we checked the variance inflation factor scores. For\u0026nbsp;both the regression equations of a full specification and a model without the ATC classification dummy variables, we noted that both F-statistics and adjusted R-squared values displayed fairly good signs of model fitness.\u003c/p\u003e\n\u003cp\u003e[Table 4 here]\u003c/p\u003e\n\u003cp\u003eRegarding the significance of individual variables, both regression equations showed that the number of patients was negatively associated with the log-transformed average treatment cost. In other words, the log of the average treatment cost could be expected to decrease by 0.005%, -0.005%=(100*(\u0026beta;_j ) ̂)%=(100*-0.00005)%, for the full specification and by 0.006% for the model without the ATC classification, in response to each additional patient increase. For both regression models, a 1% change in log-transformed adjusted average prices in A7 countries was associated with a \u0026beta;_j% change in log-transformed average treatment cost. As such, a 1% change in log(average of A7 adjusted prices) was estimated to correspond to a 1.035% increase in log(average treatment cost) for the full model and a 1.068% increase for the partial model.\u003c/p\u003e\n\u003cp\u003eIn the full model with a higher adjusted-R value and F-statistic, a classification as an oncology drug was associated with a -14.8% change in log(average treatment cost) compared with non-oncology cases. B- and N-coded drugs (for Blood and Blood Forming Organs and Nervous System, respectively) in the ATC\u0026nbsp;classification\u0026nbsp;were associated with changes of -22.4% and -69.5% in log(average treatment cost), respectively. Meanwhile, RSA-assigned drugs were associated with a 15.8% change.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBoth scatterplots and regression results indicated an almost one-to-one correspondence between\u0026nbsp;average treatment cost in South Korea and adjusted average prices in A7 countries, indicating that\u0026nbsp;the OD pricing in South Korea was highly influenced by the changes in adjusted average prices in A7 countries. The intrinsic characteristics of\u0026nbsp;drugs, such as oncology indication and ATC classification, and RSA assignment status also wielded much influence. Lastly, the number of patients made a small degree of difference. Meanwhile, differences in P\u0026amp;R pathways and budget impact\u0026nbsp;did not incur changes in\u0026nbsp;average treatment cost, contrary to our expectations.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTherefore, the drug characteristics that qualified ODs to certain P\u0026amp;R pathways and other external factors collectively characterized the pricing of ODs. Notably, the pricing of ODs in South Korea did not move in tandem over different P\u0026amp;R categories. The P\u0026amp;R pathway dummy variables collectively contributed to the overall model fitness with other explanatory variables. Meanwhile, the strong statistical association with adjusted average prices in A7 countries indicated that reference prices had the greatest impact on the pricing of ODs in South Korea.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe P\u0026amp;R pathways have been widely regarded as the most important factor determining patients\u0026rsquo; access to ODs [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Given that ODs are used by only a small fraction of the whole population, most of them are priced at an astronomical level to compensate for their R\u0026amp;D expenditure [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Therefore, patients who need ODs face difficulties in affording such prices without the help of public reimbursement [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. From the side of biopharmaceutical companies, having their drugs listed in the reimbursement system encourages consumption, which can help drug companies recoup their hefty investment expenses in a financially viable way over the long term. Otherwise, even companies with pipelines whose safety and efficacy have passed through formal evaluation processes can go bankrupt if cash flow shortfalls occur [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAs more ODs enter the market, P\u0026amp;R decisions become a major budgetary issue that policy makers have to contend with. In South Korea, the expenditure share of ODs out of the total pharmaceutical spending nationwide accounts for a mere 1%, below the 3% level of most European countries and 5% or 9% level in some countries, such as the US or Bulgaria, it can reach up to 5% or as high as 9% [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. A study conducted in China found that the financial impact of high-cost ODs on both society and payers is relatively limited. Therefore, it was recommended that health policymakers choose suitable reimbursement strategies that align with financial feasibility [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Ultimately, decisions boil down to a moral dilemma between utilitarianism\u0026mdash;maximizing outcomes with finite health care resources\u0026mdash;and non-abandonment, which can be seen at favoritism toward those in dire needs [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan additionalcitationids=\"CR40\" citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe annual treatment costs per patient of existing ODs range between USD 1,300 and 500,000, with the average cost per patient lying between USD 32,000 and 35,000 [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. As one of the notable cases, onasemnogene abeparvovec (Zolgensma \u0026reg;) for the indication of spinal muscular atrophy can cost up to USD 2.1\u0026nbsp;million in the US and USD 1.5\u0026nbsp;million in South Korea per patient for a single administration. Therefore, even when treatment options are available, patients\u0026rsquo; access to those therapies is not guaranteed because of monumental financial barriers [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMeanwhile, the return on investment of ODs, at 8.4%, far exceeds that of non-orphan drugs, 2.3%\u0026mdash;a fact that stokes suspicion that profit-oriented corporations tap patients\u0026rsquo; willingness to pay in the absence of alternative treatments [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. In 2008, a total of 43 blockbuster drugs, or drugs with sales exceeding USD 1\u0026nbsp;billion, had orphan designations [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eGiven that most advanced countries implement variants of the ERP system, once-determined pricing inevitably spills over to neighboring countries and, thus, prices worldwide are aligned in some sense. Accordingly, pharmaceutical companies exploit the situation by delaying new drug launches in countries where they are highly likely to be compelled to list low prices and withdrawing marketing approvals upon unsatisfactory negotiation results in the P\u0026amp;R review [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. In terms of regulatory harmonization, South Korea is placed ahead of the US, the EU, and the UK, but in terms of flexibility, it is placed behind China [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. South Korean authorities have introduced layers of the aforementioned pathways in an attempt to accommodate the accessibility of patients in dire needs. With a variety of such systems in place, our study attempted to characterize the impactful factors associated with OD pricing patterns.\u003c/p\u003e \u003cp\u003eOur study indicated that differences in P\u0026amp;R pathways and total budget impact did not significantly affect OD pricing; these displayed a strongly positive correlation with adjusted A7 prices. Instead, the intrinsic characteristics of drugs, such as oncology indication, ATC classification, and RSA assignment status, played more substantial roles in determining prices. This can be interpretated as evidence that the Korean P\u0026amp;R system for ODs is designed and maintained in a fair and effective manner. OD pricing decisions are based solely on objective factors, such as product characteristics and adjusted A7 prices, indicating that the system operates strictly within established policies, free from bias by other factors. The lack of influence of budget impacts on the annual treatment cost per patient suggests that the government is pursuing utilitarianism in OD pricing, to ensure the financial stability of the overall insurance system. Notably, ODs that passed through PE waiver with RSA tended to have higher average annual treatment costs, compared with those that passed the WAP or PE pathways.\u003c/p\u003e \u003cp\u003eAll ODs included in our study were developed by foreign companies and launched first in other countries before entering the South Korean market. The Korean government\u0026rsquo;s implementation of the ERP system has resulted in an almost one-to-one correspondence between adjusted A7 prices and Korean market OD prices, leaving only a limited scope for other determinants to influence pricing.\u003c/p\u003e \u003cp\u003eOur study had a number of limitations. First, in South Korea, RSAs, which require mandatory pay-back if sales exceed pre-specified thresholds, represent one of the most financially supportive mechanisms toward payers. As such, the listed and adjusted prices may have unrealized gaps and may not match the actual prices paid by patients. In our study, as much as 54.5% of ODs included (i.e., 36 drugs) were classified as RSAs. Second, we calculated the annual treatment cost per patient based on the dosage regimen approved by Korean Ministry of Food and Drug Safety. However, in real-world cases, treatment cost is influenced by physicians\u0026rsquo; clinical guidelines or reimbursement criteria insurance standards. As such, the actual prices may differ from the prices that we calculated.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eOur study delineated the factors with actual influences on OD pricing, highlighting the interplay between OD pricing and external reference prices, drug characteristics, and number of patients. In light of these results, we recommend the adoption of a flexible approach to OD pricing decisions to ensure that patients with ultra-rare diseases are not marginalized in terms of treatment access. Our findings can guide policymakers, pharmaceutical companies, and health care providers in their efforts to balance patient accessibility with orphan drug development and the financial sustainability of public health insurance.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eOD: orphan drug\u003c/p\u003e\n\u003cp\u003eR\u0026amp;D: research and development\u003c/p\u003e\n\u003cp\u003eP\u0026amp;R: pricing and reimbursement\u003c/p\u003e\n\u003cp\u003eATC: anatomical therapeutic chemical\u003c/p\u003e\n\u003cp\u003ePE: pharmaco-economic evaluation\u003c/p\u003e\n\u003cp\u003eWAP: weighted average price\u003c/p\u003e\n\u003cp\u003eRSA: risk-sharing agreements\u003c/p\u003e\n\u003cp\u003eERP: external reference pricing\u003c/p\u003e\n\u003cp\u003eHIRA: Health Insurance Review and Assessment Service\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eEthics approval and consent to participate\u003c/h2\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch2\u003eConsent for publication\u003c/h2\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch2\u003eAvailability of data and materials\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eThe datasets analyzed in this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003ch2\u003eCompeting interests\u003c/h2\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch2\u003eAuthor\u0026rsquo;s Contributions\u003c/h2\u003e\n\u003cp\u003eSHL and SKL contributed to the study design, data collection, statistical analysis, manuscript development, and review. JHL and JSB supervised the entirety of the study, from study design, data collection and analysis, and manuscript editing to manuscript submission. All\u0026nbsp;authors have read and approved the final version of the manuscript.\u003c/p\u003e\n\u003ch2\u003eAcknowledgements\u003c/h2\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eNguengang Wakap S, Lambert DM, Olry A, Rodwell C, Gueydan C, Lanneau V, Murphy D, Le Cam Y, Rath A. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. 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BMJ open 2015; 5:e007199.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZimmermann BM, Eichinger J, Baumgartner MR. A systematic review of moral reasons on orphan drug reimbursement. Orphanet J Rare Dis 2021; 16:292. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s13023-021-01925-y\u003c/span\u003e\u003cspan address=\"10.1186/s13023-021-01925-y\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eInstitute I: Orphan Drugs in thr United States: Rare disease innovation and coast trends through 2019. 2020.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchey C, Milanova T, Hutchings A. Estimating the budget impact of orphan medicines in Europe: 2010\u0026ndash;2020. Orphanet journal of rare diseases 2011; 6:1\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRzakhanov Z. Regulatory policy, value of knowledge assets and innovation strategy: The case of the Orphan Drug Act. Research Policy 2008; 37:673\u0026ndash;689.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eInstitute I: Global Trends in R\u0026amp;D 2024: Activity, productivity, and enablers. 2024.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003eTable 4 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Orphan Drug, Rare Diseases, Pricing, Reimbursement, Budget Impact, External Reference Pricing","lastPublishedDoi":"10.21203/rs.3.rs-5336091/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5336091/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eOrphan drug pricing in South Korea, including its workings and determinants, is a complicated aspect of the country\u0026rsquo;s health care system. Therefore, this study identified the factors associated with the pricing and reimbursement system of orphan drugs in South Korea.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe study screened a total of 66 orphan drugs out of the whole set of newly reimbursed drugs from 2012 to 2022. The analyses presented the characteristics of the orphan drugs and accounted for correlations between treatment cost and other seemingly related variables. Formal multivariate regression analyses pointed out associated factors in multivariate settings.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eAnnual treatment cost per patient displayed a weakly negative correlation with the number of patients. Meanwhile, treatment cost exhibited a strongly positive correlation with the average of adjusted prices in seven advanced countries, reaching an adjusted R-squared value of 0.99. Treatment cost also showed a positive correlation with budget impact.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusions\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe pricing of orphan drugs in South Korea is predominantly influenced by external reference pricing. Drugs targeting smaller patient populations tend to be priced higher. Thus, the study highlights the interplay between drug pricing and external reference prices, drug characteristics, and pricing and reimbursement pathways. The findings can guide policymakers, pharmaceutical companies, and health care providers in their efforts to balance patient accessibility with orphan drug development and the financial sustainability of public health insurance.\u003c/p\u003e","manuscriptTitle":"Factors Associated with the Pricing and Reimbursement System of Orphan Drugs in South Korea","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-20 07:45:10","doi":"10.21203/rs.3.rs-5336091/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"775908e1-0675-4adc-b662-71f2166d9761","owner":[],"postedDate":"November 20th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-01-23T09:09:06+00:00","versionOfRecord":[],"versionCreatedAt":"2024-11-20 07:45:10","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5336091","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5336091","identity":"rs-5336091","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}