Rheumatoid arthritis (RA) is a chronic connective tissue autoimmune disorder that leads to considerable functional disability, reduced quality of life, and loss of earning capacity1 Conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), such as methotrexate, have long been regarded as the standard of care for RA and are widely used in newly diagnosed patients to slow disease progression, control disease manifestations, and achieve remission.2 3 However, csDMARDs exhibit relatively slow onset of action and require close monitoring due to the potential for adverse events, especially in patients with chronic co-morbidities.2 4 For patients who exhibit poor prognostic factors with moderate to high disease activity after initial therapy with csDMARDs, novel biologic DMARDs (eg, infliximab, adalimumab, certolizumab pegol, or golimumab) or targeted synthetic, small-molecule DMARDs (eg, tofacitinib) are recommended for use in combination with csDMARDs, or as monotherapy.2 3 5

Tofacitinib is a small synthetic molecule Janus kinase inhibitor which modulates leukocyte recruitment, activation, and effector cell function at sites of inflammation. It is the first orally bioavailable therapeutic agent to improve clinical remission in patients with RA.6 The safety and efficacy of tofacitinib, relative to those of csDMARDs, have been reported in recent landmark trials and observational studies. Tofacitinib monotherapy was superior to methotrexate for reduction of RA symptoms and inhibition of the progression of structural joint damage in patients who had not previously received methotrexate or therapeutic doses of methotrexate.7 In patients with inadequate responses to methotrexate, tofacitinib was non-inferior to adalimumab for symptom control when used as a combination therapy with methotrexate.8 However, the increased risk of adverse events associated with tofacitinib, including infections (eg, herpes zoster and tuberculosis) and malignancy, is a major limitation that requires long-term surveillance and careful prescribing practices.7 8

Similar to biologic DMARDs, tofacitinib is more expensive than csDMARDs (eg, methotrexate $1 versus tofacitinib $66 per tablet in the US9). Several studies have supported the cost-effectiveness of tofacitinib. When used as an alternative first-line treatment to csDMARD, tofacitinib was found to be cost-effective in the South Korean population due to its ability to significantly improve patients’ quality of life.10 When used in combination with a csDMARD, a study in the US showed that tofacitinib was highly cost-effective in patients with severe RA, relative to combinations of most biologics with csDMARD.11 In a recent modelling study, tofacitinib was also found to be cost-saving as a second-line therapy following methotrexate failure and as a third-line therapy following the failure of a biologic therapy.12

Treatment decisions for patients with uncontrolled RA are increasingly complex because there are no direct head-to-head comparisons among novel DMARDs from landmark trials, and there are limited long-term data describing medication safety and compliance. Selection of biologic DMARDs or tofacitinib is largely dependent on multiple clinical and socio-economic factors, including disease activity, progression of structural damage, and co-morbidities within a particular patient, as well as their preferences for route of administration and dosing frequency, and the regulatory and cost barriers to drug access.13

Tofacitinib was approved in Hong Kong as a prescription-only drug in 2014.14 At the time of writing, tofacitinib is listed as a self-financed item without safety net in the public hospital formulary; thus, the cost of tofacitinib is entirely out-of-pocket for patients.15 The impact of funding tofacitinib in the public healthcare system remains unknown. In the present study, we assessed the budgetary impact of introducing tofacitinib into the Drug Formulary of the Hospital Authority—the statutory body that manages Hong Kong’s public hospital services. The objective of this study was to provide guidance for drug listing decisions from a public institutional perspective.

The target population comprised adults with RA who showed inadequate response to initial csDMARD monotherapy and were recommended for treatment with novel DMARDs.2 5 Adult patients who had been treated with novel DMARDs, during the period from 1 January 2009 to 31 December 2015, were identified from the Clinical Data Analysis and Reporting System (CDARS) of Hong Kong (a territory-wide electronic health record). Developed by the Hospital Authority, a statutory body that manages all public hospitals and provides health service to all Hong Kong residents (over 7 million),16 CDARS is recognised as a unique population-based electronic health record in Hong Kong that enables publication of an increasing number of high-quality studies.17 18 19 20 21 A detailed description of CDARS can be found elsewhere.22 23 24 In this study, retrieved data from the electronic patient records included demographics, date of registered death, date of hospital admission and discharge, drug dispensing records and diagnoses. Patient records from CDARS are de-identified and linked with unique reference keys to protect patient privacy and facilitate data retrieval. Based on the eligible patients identified from CDARS, the number of patients on novel DMARDs was calculated annually between the year of 2009 and 2015 and projected for the years from 2017 to 2021 assuming a linear trend of increasing in patients receiving novel DMARDs (online supplementary Appendix 1).

We developed a population-based budget impact model to trace the number of patients with RA on novel DMARDs and assess changes in healthcare expenditures with respect to RA treatments (Fig 1). The model used a cohort of patients diagnosed with RA who showed inadequate responses to initial DMARD therapy. Without the introduction of tofacitinib, patients were assumed to use one of the biologic DMARDs (monotherapy or combination therapy with a csDMARD), according to its corresponding market share. The introduction of tofacitinib provided an additional option to patients newly placed on novel DMARDs, with treatment choices determined by projected market share. We assumed that the annual retention rate of biologics was 100%, whereas that of tofacitinib was 80%, in accordance with landmark trial results.7 Dropout patients were assumed to switch to one of the biologics, according to its corresponding market share in the same year. We also assumed that the safety and efficacy profiles of biologics and tofacitinib were equivalent, based on a recent Cochrane review that assessed novel DMARDs compared to placebo or standard care,25 and based on a head-to-head comparison between tofacitinib and adalimumab.8 The assumptions of the projection model are summarised in online supplementary Appendix 2.

The analysis was conducted from the public institutional perspective of Hong Kong, and direct medical costs were calculated. The numbers of patients on each treatment and overall medication costs were calculated on a yearly basis, and results were cumulative over a period of 5 years (2017-2021). Monetary value was expressed in Hong Kong dollars (HK$) in 2017, discounted at 4% per year.26 27 The study outcome was the difference in healthcare expenditures with respect to RA treatment, with or without introducing tofacitinib into the formulary. There was no pre-defined threshold for a favourable budget impact.

Treatment options were assumed to include biologics (eg, abatacept, adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, and tocilizumab) and tofacitinib, using current recommendations for patients with inadequate responses to csDMARDs. Table 1 shows dosage regimens, per dose cost in local currency, and annual medication costs for each treatment. The number of patients on each treatment was determined by the corresponding market share of the treatment and the total number of eligible patients in the same year. Based on the number of biologics that were prescribed from 2013 to 2015 (as recorded in CDARS), the compound annual growth rate (CAGR) was estimated by following equation28:

We assumed a constant CAGR for each biologic; the corresponding market share was projected yearly between 2017 and 2021 (online supplementary Appendix 3). The overall market share of novel DMARDs was assumed to be 100%.

In the base-case analysis, we assumed that one-third of the eligible patients who were new users of novel DMARDs would be placed on tofacitinib in the first year. In accordance with the findings of the landmark trial, 20% of tofacitinib users were expected to drop out each year, due to adverse events.7 We assumed that the dropout patients would choose one of the biologics and that the efficacy and safety of tofacitinib and all biologics were equivalent; hence, the switch would only affect medication costs. Three scenario analyses were conducted to assess the impact of uncertainties on the base-case conclusion: specifically, uncertainties were considered in market share of tofacitinib and dropout of tofacitinib users (Table 2). The base-case scenario was regarded as the worst scenario for the uptake of tofacitinib (market share of 33.3% among new novel DMARDs users and 20% annual dropout). In the other three scenarios, the first-year uptake of tofacitinib increased from 50% to 100%, and the annual dropout rate ranged from 0% to 20%. Scenario 4 was determined to be the best scenario, with the highest first-year uptake and 100% retention over 5 years. We also tested the impact of discounting (0-4%) on base-case results, as there are no health technology assessment guidelines with respect to the proper discount rate for Hong Kong.

Statistical Analysis System software (version 9.4, SAS Inc, Cary [NC], US) was used for data manipulation and analysis. Microsoft Excel (2003 for Windows; Microsoft Corp, Redmond [WA], US) was used to establish the budget impact model and generate corresponding plots.

The study was designed and reported in accordance with the Consolidated Health Economic Evaluation Reporting Standards Statement.29 The study protocol in which CDARS was used to estimate the number of eligible patients was approved by the Hospital Authority Hong Kong West Cluster and The University of Hong Kong Institutional Review Board (UW14-602). Ethics approval for the budget impact analysis was waived, as it comprised a statistical modelling projection without patient contact.

Between 2017 and 2021, the estimated number of eligible patients on novel DMARDs increased from 1466 to 2375. Without introducing tofacitinib into the formulary, the annual government health expenditures for RA treatment were projected to increase from HK$147.9 million (2017) to HK$190.6 million (2021) [Fig 2a]. The increased expenditures were driven by increased patient volume and growth of the biologics market. Addition of tofacitinib to the formulary would reduce relevant healthcare expenditures by HK$33.1 million to HK$39.9 million annually (17.3% to 20.3% reduction) [Fig 2a]. Budgetary savings were expected, regardless of discount rates (Fig 2). Cumulative savings over the 5-year study period were projected to be HK$192.8 million (discounted at 4%) and HK$208.8 million (undiscounted), respectively.

Variations in the market share of tofacitinib were assessed in different test scenarios (Fig 3). The base-case scenario assumed the most conservative uptake of tofacitinib, comprising 4.4% to 10.7% of the overall novel DMARD market. With the assumption that half of the new users of novel DMARDs would choose tofacitinib, combined with the assumption of an annual dropout rate of 20% (Scenario 2), the market share of tofacitinib was expected to increase from 6.6% to 13.1% over the 5-year study period. With the assumption that all new users of novel DMARDs would choose tofacitinib (Scenario 3), the market share was expected to increase from 13.2% to 32% over the 5-year study period. In the best-case scenario (Scenario 4), 100% uptake was assumed, combined with the assumption of an annual dropout rate of 0% among new users, the market share of tofacitinib was expected to increase linearly from 13.2% in 2017 to 46% in 2021.

The estimated annual health expenditures for RA treatments were positively correlated with the uptake of tofacitinib. In all tested scenarios, the introduction of tofacitinib to the public hospital formulary provided consistent savings, compared to the current situation where tofacitinib is self-financed (Fig 4). Similar to the base-case scenario, the cumulative budget savings over the 5-year study period were estimated to be HK$193.5 million and HK$196.8 million for Scenarios 2 and 3. In the best-case scenario with the highest uptake of tofacitinib, the total savings were reduced to HK$66.4 million (Fig 4).

In Hong Kong, patients with uncontrolled RA must pay HK$20 000 to HK$100 000 per year out-of-pocket to receive novel DMARDs treatments that facilitate disease remission. In addition to the progressive loss of working ability associated with RA, the high cost of therapy poses an additional burden to affected patients, their families, and society.30 In the present study, we attempted to provide guidance with respect to introduction of tofacitinib to the public hospital formulary by analysing the budgetary impact of this change. Drug listing and subsidy decisions rely on the principles of efficacy, safety, and cost-effectiveness; thus, they must consider a variety of factors, including clinical evidence and impact on healthcare costs.31 Budgetary impact is a key element of health economic evaluations that must be determined before formulary approval in many developed countries with established health technology assessments.32 33 34 Local and international health economists have suggested that systematic procedures and transparency are needed with respect to formulary decision-making in Hong Kong.35 Based on the current drug costs of novel DMARDs and the volume of patients who receive treatment in public hospitals in Hong Kong, our model projection suggests that the introduction of tofacitinib would provide savings over the 5-year study period.

In our analysis, governmental healthcare expenditures for RA treatments were lowered by approximately 20% upon the introduction of tofacitinib to the public hospital formulary. With the assumption that none of the novel DMARDs were discontinued or withdrawn from the market, the annual treatment costs of tofacitinib were lower than those of all biologics, except infliximab. This may explain the increased market share of tofacitinib, as well as the reduction in overall RA treatment costs. In clinical practice, both biologic DMARDs and tofacitinib are commonly used in combination with a csDMARD.2 3 In our analysis, we did not consider the cost of csDMARDs, as they are currently listed as fully subsided drugs in the formulary and are thus expected to have minimal impact on the cost of RA treatment, regardless of the addition of tofacitinib to the formulary.

The introduction of tofacitinib to the formulary will intensify market competition, which may improve the effectiveness of disease management36; moreover, this change will provide a more convenient orally administered option for patients who are reluctant to undergo subcutaneous or intravenous injections, and who are willing to switch from biologic DMARDs to an alternative therapy.37 38 Patient preferences regarding RA treatment may affect compliance, adherence, and quality of life.39 40 The route of administration significantly influences the decision between tofacitinib and biologics.41 Among all factors that impact patients’ therapeutic preferences, the convenience of oral administration has been shown to exhibit the strongest influence.39 Thus, the oral route of administration for tofacitinib is likely to provide an advantage over the parenteral route of administration for biologics.

Given current evidence regarding the cost-effectiveness of tofacitinib, broader utilisation of tofacitinib can be expected in the future if safety concerns are appropriately addressed. The underlying effector mechanism of tofacitinib comprises intracellular transduction inhibition, which carries the potential for interaction with the immune system; these factors may contribute to its associations with serious infections, herpes zoster, tuberculosis, gastrointestinal disorders, and few malignancies.7 8 However, an integrated safety summary from Phase I-III trials showed stable adverse events, with an incidence rate of 0.1-3.9 per 100 patient-years, and no new safety signals in patients who had used tofacitinib for up to 8.5 years.42 Moreover, a recent systematic review with network meta-analysis concluded that tofacitinib monotherapy had efficacy comparable to that of currently available biologics, as well as similar discontinuation rates due to adverse events.43 Current clinical evidence from trials and real-world observations support the safety of tofacitinib.

We acknowledge that this study had several limitations. First, we did not consider the costs of monitoring treatments or treatment of adverse events; this may have led to underestimation of overall healthcare expenditures for RA treatments. However, given that monitoring costs and numbers of adverse events from biologics and tofacitinib may be similar,43 the absolute changes in healthcare expenditures are not expected to differ from those we have described. Second, the expected tofacitinib dropout rate was established on the basis of landmark trials. Patient compliance and possible treatment switches in real-life clinical treatment settings were not analysed in this study. Thus, the results of this study should be interpreted cautiously with respect to the safety, efficacy, and adherence of tofacitinib and biologics. Third, we assumed constant costs for all treatments over the study period; in practice, these may be affected by the dynamic state of the market and a variety of possible interactions between costs and market share. Finally, structural and parametric uncertainties from the model were not tested comprehensively. Although we do not expect deviation from the base-case conclusion, future studies should assess model uncertainties while considering current clinical evidence with respect to the effectiveness and safety of novel DMARDs.

The introduction of tofacitinib to the Hospital Authority Formulary in Hong Kong for the treatment of patients with uncontrolled RA is expected to lower healthcare expenditures over the 5-year study period. The conclusion is robust in all scenario analyses with respect to uncertainties in drug costs, as well as in tofacitinib uptake and compliance.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

Conception and design: X Li, EWY Chan.
Acquisition of data: X Li, KK Man.
Analysis or interpretation of data: X Li, KK Man, S Pathadka, EWY Chan.
Drafting of the manuscript: X Li.
Critical revision for important intellectual content: All authors.
Study supervision: ICK Wong, EWY Chan.

We acknowledge Mr Joseph E Blais and Dr In Hye Suh from the Department of Pharmacology and Pharmacy, The University of Hong Kong, for their critical review, thoughtful comments, and proofreading of the manuscript.

EWY Chan has received funding from the Early Career Scheme and the General Research Fund from the Hong Kong Research Grants Council; the Health and Medical Research Fund, Food and Health Bureau, Hong Kong SAR Government; the Beat Drugs Fund from the Narcotics Division, Security Bureau; and the Young Scientist Fund, National Science Foundation Science Foundation of China, all unrelated to the current work. EWY Chan has also received research grants from Bayer, Bristol-Myers Squibb, Janssen Pharmaceutica, Pfizer, and Takeda, and honorarium from the Hong Kong Hospital Authority, all unrelated to the current work. ICK Wong received grants from the Hong Kong Research Grants Council, Innovative Medicines Initiative, Shire, Janssen Pharmaceutica, Eli Lilly, Pfizer, Bayer, and the European Union FP7 programme, all unrelated to the current work. ICK Wong was a member of the National Institute for Health and Clinical Excellence ADHD Guideline Group and the British Association for Psychopharmacology ADHD guideline group and acted as an advisor to Shire. X Li received a research grant from the Health and Medical Research Fund, Food and Health Bureau, Hong Kong SAR Government and consulting fees from Pfizer, unrelated to this work. KK Man received the CW Maplethorpe Fellowship and personal fees from IQVIA Holdings, Inc. (previously known as QuintilesIMS Holdings, Inc.), unrelated to this work. The other author(s) declare no conflicts of interest.

Preliminary results from this study were presented (poster, title: Budget impact analysis of introducing tofacitinib for the treatment of patients with rheumatoid arthritis in Hong Kong) at ISPOR 7th Asia-Pacific Conference (Tokyo, Japan, 8-11 September 2018). The conference abstract was published in Value in Health (Volume 21, S80, DOI: https://doi.org/10.1016/j.jval.2018.07.599).

This work was supported by Pfizer Corporation Hong Kong Limited (grant No. RC170156). The funder had no role in the study design, data collection and analysis, preparation of the manuscript, or decision to publish.

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