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Impact of Universal Health Insurance Coverage in Thailand on Sales and Market Share of Medicines for Non- Communicable Diseases: An Interrupted Time Series Study

For peer review only Journal: BMJ Open

Manuscript ID: bmjopen-2012-001686

Article Type: Research

Date Submitted by the Author: 29-Jun-2012

Complete List of Authors: Garabedian, Laura; Harvard Medical School and Harvard Pilgrim Health Care Institute, Department of Population Medicine Ross-Degnan, Dennis; Harvard Medical School and Harvard Pilgrim Health Care Institute, Department of Population Medicine Ratanawijitrasin, Sauwakon; Mahidol University, Faculty of Social Sciences and Humanities Stephens, Peter; IMS Health, Wagner, Anita; Harvard Medical School and Harvard Pilgrim Health Care Institute, Department of Population Medicine

Primary Subject Global health Heading:

Health policy, Health economics, Health services research, Pharmacology Secondary Subject Heading: http://bmjopen.bmj.com/ and therapeutics, Public health

Health policy < HEALTH SERVICES ADMINISTRATION & MANAGEMENT, Health economics < HEALTH SERVICES ADMINISTRATION & Keywords: MANAGEMENT, Essential Medicines, CARDIOLOGY, DIABETES & ENDOCRINOLOGY, ONCOLOGY

on September 26, 2021 by guest. Protected copyright.

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1 2 3 TITLE PAGE 4 5 6 Impact of Universal Health Insurance Coverage in Thailand on Sales and Market Share of 7 Medicines for Non-Communicable Diseases: an Interrupted Time Series Study 8 9 Laura Faden Garabedian, MPH1, Dennis Ross-Degnan, ScD1, Sauwakon Ratanawijitrasin, PhD2, 10 3 1 11 Peter Stephens, MA , Anita Wagner, PharmD, MPH, DrPH 12 13 Institutions: 14 1 Drug Policy Research Group and WHO Collaborating Center in Pharmaceutical Policy 15 Department of PopulationFor Medicine,peer Harvard review Medical School andonly Harvard Pilgrim Health Care 16 Institute 17 18 133 Brookline Ave., Sixth Floor 19 Boston, MA, USA 20 21 Dennis Ross-Degnan and Anita Wagner are Associate Professors. Laura Faden Garabedian is a 22 Research Fellow and PhD Candidate. 23 24 25 Corresponding author: Laura Faden Garabedian 26 Phone: +1 617 509 9921 27 Email: [email protected] 28 29 2 30 Professor 31 Faculty of Social Sciences and Humanities, Mahidol University 32 Salaya, Buddhamonthon, Nakhonpathom, 73170 Thailand 33 3 34 Director, Public Health Affairs http://bmjopen.bmj.com/ 35 IMS Health 36 37 7 Harewood Avenue 38 London, NW1 6JB, UK 39 40 Study Design: Observational study (interrupted time series design) 41 42 on September 26, 2021 by guest. Protected copyright. 43 Acknowledgements: We gratefully acknowledge support of statistical analyses by Dr. Fang 44 Zhang, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim 45 Health Care Institute, Boston, USA. Dr. Sanita Hirunrassamee, Phramongkutklao Hospital, 46 Bangkok, Thailand, provided helpful input on Thai essential medicines listings and coverage 47 policies. Mr. Amit Backliwal, at the time of the study at IMS Health, Bangkok, Thailand, shared 48 valuable insights on the Thai pharmaceutical market. 49 50 51 Author contributions: Laura Garabedian, Dennis Ross-Degnan and Anita Wagner designed the 52 study and developed the analytic approach. Peter Stephens assembled the data files. Laura 53 Garabedian analyzed the data. Sauwakon Ratanawijitrasin provided the Thai national list of 54 essential medicines and information on relevant Thai policies and context surrounding the 55 56 reform. All authors participated in the interpretation of the results. Laura Garabedian wrote the 57 first draft of the paper. All authors contributed to the writing of the manuscript. 58 59 60 1 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 52 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 4 5 Opinions expressed are solely those of the authors and not of the institutions they represent. 6 7 Competing Interest Statement: All authors have completed the Unified Competing Interest 8 form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) 9 and declare: LFG had financial support from Harvard Medical School and Harvard University, 10 11 AW and DRD were supported in part by a grant from the Novartis Foundation for Sustainable 12 Development, PS is an employee of IMS Health; no financial relationships with any 13 organisations that might have an interest in the submitted work in the previous 3 years; no other 14 relationships or activities that could appear to have influenced the submitted work. 15 For peer review only 16 Funding: IMS Health provided the data in-kind. The Harvard Medical School Fellowship in 17 Pharmaceutical Policy Research and the Harvard University PhD Program in Health Policy 18 19 supported Ms. Garabedian. Drs. Wagner and Ross-Degnan were supported in part by a grant 20 from the Novartis Foundation for Sustainable Development to develop examples of research on 21 access to medicines using IMS Health data for presentation at the Third International Conference 22 for Improving Use of Medicines. 23 24 IRB Approval: Harvard Pilgrim Health Care Institute Office of Sponsored Programs 25 26 27 Exclusive Licence Statement: The Corresponding Author has the right to grant on behalf of all 28 authors and does grant on behalf of all authors, a worldwide licence to the Publishers and its 29 licensees in perpetuity, in all forms, formats and media (whether known now or created in the 30 future), to i) publish, reproduce, distribute, display and store the Contribution, ii) translate the 31 32 Contribution into other languages, create adaptations, reprints, include within collections and 33 create summaries, extracts and/or, abstracts of the Contribution, iii) create any other derivative

34 work(s) based on the Contribution, iv) to exploit all subsidiary rights in the Contribution, v) the http://bmjopen.bmj.com/ 35 inclusion of electronic links from the Contribution to third party material where-ever it may be 36 located; and, vi) licence any third party to do any or all of the above. 37 38 39 Data Sharing Statement: Data available upon request, at the approval of IMS Institute for 40 Healthcare Informatics. 41 42 on September 26, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 2 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 52 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 Article Summary 4 5 Article Focus 6 7 8 • Medicines present a key challenge to achieving universal coverage. 9 • Health insurance systems have the potential to improve cost-effective use of medicines, 10 yet there is little evidence about their impact on medicine use in low and middle income 11 countries. 12 • The recent implementation of universal health coverage in Thailand presents a unique 13 14 opportunity to measure the impact of health insurance expansion and associated 15 physicianFor payment changespeer on utilization review of medicines. only 16 17 Key Messages 18 19 • Expanding health insurance coverage with a medicines benefit to the entire Thai 20 population increased access to medicines in primary care. 21 • The universal coverage scheme did not seem to have increased use of medicines for 22 23 diseases that are typically treated in secondary or tertiary care settings, or increased 24 generic market penetration. 25 • In the future, it will be important for countries to assess quality and equity of medicines 26 use as they pursue policies to achieve universal coverage. 27 28 Strengths and Limitations 29 30 • We used an interrupted time series design, the strongest quasi-experimental approach for 31 32 evaluating effects of interventions, increasing internal validity. 33 • It is impossible to examine population subgroups in national IMS Health market data, but

34 we are reasonably confident that universal coverage scheme enrollees are responsible for http://bmjopen.bmj.com/ 35 observed changes. 36 37 38 39 40 41 42 on September 26, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 3 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 52 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 ABSTRACT 4 5 Objective: In 2001, Thailand implemented the Universal Coverage Scheme (UCS), a public 6 7 insurance system covering primarily the poor and uninsured that aimed to achieve universal 8 9 access to health care, including essential medicines, and to influence provider behavior to use 10 11 resources efficiently via capitated payment. Our objective was to evaluate the impact of the UCS 12 13 on utilization of medicines in Thailand for three non-communicable diseases: cancer, 14 cardiovascular disease, and diabetes. 15 For peer review only 16 Design: Interrupted time series design, with a non-equivalent comparison group. 17 18 Setting: Thailand, 1998-2006. 19 20 Data: Quarterly purchases of medicines from hospital and retail pharmacies collected by IMS 21 Health between 1998 and 2006. 22 23 Intervention: UCS implementation, April-October 2001. 24 25 Outcome measures: Total pharmaceutical sales volume and percent market share by licensing 26 27 status. 28 29 Results: The UCS was associated with long-term increases in sales of medicines for conditions 30 that are typically treated in outpatient primary care settings, such as diabetes, high cholesterol 31 32 and high blood pressure, but not for medicines for diseases that are typically treated in secondary 33

34 or tertiary care settings, such as heart failure, arrhythmias, and cancer. While the majority of http://bmjopen.bmj.com/ 35 36 increases in sales were for essential medicines, there were also significant post-policy increases 37 in sales of non-essential medicines. Immediately following the reform, there was a significant 38 39 shift in hospital sector market share by licensing status for most classes of medicines. 40 41 Government-produced products often replaced branded generic or generic competitors. 42 on September 26, 2021 by guest. Protected copyright. 43 Conclusions: Our results suggest that expanding health insurance coverage with a medicines 44 45 benefit to the entire Thai population increased access to medicines in primary care. However, our 46 study also suggests that the UCS may have had potentially undesirable effects. Evaluations of the 47 48 long-term impacts of universal health coverage on medicines utilization are urgently needed. 49 50 51 52 53 54 55 56 57 58 59 60 4 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 52 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 MANUSCRIPT 4 5 6 Introduction 7 8 9 10 Universal Health Coverage 11 In 2005, Member States of the World Health Organization (WHO) made a commitment to work 12 13 towards universal health care coverage.1 The 2010 WHO World Health Report provides a 14 2 15 roadmap for countriesFor to achieve peer this goal. review Universal coverage onlyrequires the restructuring of 16 17 health care and financing systems to improve access to health care services, reduce financial 18 hardship, and increase the efficiency and equity of the health system.2 19 20 21 22 Medicines, which consume 25–65% of total public and private spending on health in developing 23 3 24 countries, present a key challenge to achieving universal coverage. According to the WHO, 25 26 three of the top ten sources of health care inefficiency involve medicines: high medicine prices 27 and underuse of generics; use of substandard and counterfeit medicines; and inappropriate and 28 29 ineffective use of medicines.2 Health insurance systems have several features (e.g., a defined 30 31 population, access to utilization data, and financial leverage) that give them a unique advantage 32 33 to reduce out-of-pocket (OOP) expenditures and improve the cost-effective use of medicines

34 through active management strategies involving medicines selection, purchasing, contracting http://bmjopen.bmj.com/ 35 36 (e.g., physician payment) and utilization management.4 However, there is little evidence about 37 38 the impact of health insurance on access to and use of medicines in low- and middle-income 39 4 40 countries (LMICs). 41 42 on September 26, 2021 by guest. Protected copyright. 43 The recent implementation of universal health coverage in Thailand presents a unique 44 45 opportunity to measure the impact of health insurance expansion and physician payment changes 46 47 (from fee-for-service to capitation) on utilization of medicines. 48 49 50 Universal Health Coverage in Thailand 51 52 With the implementation of the UCS in 2001, Thailand became one of the first LMICs to achieve 53 54 universal coverage.5,6 The reforms preserved the formal sector workforce schemes: the Social 55 56 Health Insurance (SHI) scheme for private sector employees (6·3% of the total population) and 57 58 the Civil Service Medical Benefit Scheme (CSMBS) for government employees and their 59 60 5 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 52 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 dependents (13·6%).7 In addition, the UCS covered those previously enrolled in a voluntary 4 5 health card (VHC) scheme (22·0%), in private health insurance (1·6%), or in a tax-based, means- 6 7 tested Low Income Scheme (LIS) for the poor, elderly, children and disabled (28·9%)7,8 as well 8 7 9 as more than one quarter (26·6%) of the population without previous insurance. The UCS was 10 5 11 rolled out to all provinces between April and October 2001. By 2005, 95·5% of the population 12 was insured, with just over 70% of the population covered by the UCS.7 13 14 15 For peer review only 16 The UCS is a compulsory, tax-financed scheme with comprehensive coverage of inpatient and 17 5 18 outpatient services, including medicines on the National List of Essential Medicines (NLEM). 19 Individuals must enroll in the scheme at a local Contracting Unit for Primary Care (CUP),5 20 21 primarily housed in government-owned hospitals.9 Each CUP receives a capitated payment per 22 5 23 registered member to provide outpatient services and medicines. CUPs served as gate-keepers 24 25 for secondary and tertiary hospitals. When patients were referred, payments for higher-level care 26 initially came out of the CUP’s capitated payment, so CUPs had a financial disincentive to refer 27 28 patients.5 29 30 31 32 Our objective was to evaluate the immediate, short-term (one year) and long-term (five year) 33 impacts of the UCS on pharmaceutical market size and composition for medicines for three non- 34 http://bmjopen.bmj.com/ 35 communicable diseases (NCDs): cancer, cardiovascular disease, and diabetes. We hypothesized 36 37 that the UCS would result in a gradual increase in sales volume, particularly of products used in 38 39 primary care, as enrollment into the Scheme increased, and in an immediate increase in market 40 41 share of less expensive generic or branded generic products and medicines on the NLEM in 42 response to capitated payment rules. We focused on medicines for NCDs since these illnesses on September 26, 2021 by guest. Protected copyright. 43 44 represent a large and growing health care burden in Thailand10–13 and other LMICs14 and most, 45 46 but not all, medicines for NCDs would be prescribed and dispensed in primary care settings. 47 48 49 Methods 50 Data 51 52 We used data on quarterly pharmaceutical sales in Thailand from 1998 to 2006 provided by IMS 53 54 Health.15 The sales data are generated from reports to IMS Health by multinational 55 56 pharmaceutical companies and surveys of purchases by hospital and retail pharmacies. IMS 57 58 surveys approximately 200 hospitals (including general and specialized, public and private) and 59 60 6 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 52 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 350 retail pharmacies in Thailand, and employs a stratified random sample of these facilities that 4 5 enables national projections. Medicines were classified according to the European 6 7 Pharmaceutical Research Association (EphMRA) Anatomical Therapeutic Chemical (ATC) 8 16 9 system. 10 11 12 Outcomes 13 14 We used two outcome measures: total volume and percent market share. Total volume is the 15 For peer review only 16 number of standard units purchased per capita per quarter (i.e., “sales”). We analyzed total 17 18 volume by sector (i.e., retail versus hospital) and, within the hospital sector, by NLEM versus 19 non-NLEM status of medicines (based on the 1999 Thai NLEM). A standard unit, as defined by 20 21 IMS Health, is the smallest dose of a product, which equates to one tablet or capsule for an oral 22 23 dosage form, one teaspoon (5ml) for a syrup, and one ampoule or vial for an injectable product. 24 25 We divided total volume by size of the population over 15 years old to control for population 26 growth (using yearly population estimates from the World Bank17). We used the entire 27 28 population as denominator for insulins, since they are also used for Type 1 diabetes, a chronic 29 30 disease that affects children. Percent market share is the percent of total volume in four mutually 31 32 exclusive categories of licensing status: originator brand products, branded generic products 33 (products sold under a brand name other than the originator brand name of the molecule), generic 34 http://bmjopen.bmj.com/ 35 products (products that are sold under the generic molecule name), and products manufactured 36 37 by Thailand’s Government Pharmaceutical Organization (GPO). 38 39 40 41 We analyzed total volume and market share for medicines in eight therapeutic classes: two 42 classes of diabetes products (oral antidiabetics and insulins), three classes of cardiovascular on September 26, 2021 by guest. Protected copyright. 43 44 disease products (antihypertensives, lipid-regulating, and cardiac therapy products) and three 45 46 classes of cancer products (antineoplastics, immunostimulating agents, and cytostatic hormone 47 48 therapy products); Table 1 in the online appendix lists all medicines by ATC code. Antidiabetic, 49 50 insulin, antihypertensive and lipid-lowering products are used for conditions that are typically 51 treated in primary care settings (i.e., diabetes, high blood pressure and high cholesterol), whereas 52 53 cardiac therapy and cancer products are used for more severe conditions that are more likely to 54 55 be treated by a specialist and/or in inpatient settings. 56 57 58 59 60 7 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 52 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 Research Design 4 5 We used an interrupted time series design, the strongest quasi-experimental approach for 6 7 evaluating effects of interventions, which has been used extensively for medication use 8 18 9 research. Although we did not have an equivalent control group, we used medicines sold in the 10 19 11 retail sector as a non-equivalent comparison group, assuming that the retail market should be 12 relatively unaffected by the reforms since UCS enrollees could only obtain covered medicines 13 14 through their local, hospital-based CUP. 15 For peer review only 16 17 18 Statistical Analysis 19 The intervention was the UCS roll-out from April to October 2001. We defined three distinct 20 21 periods: 12 quarters pre-reform (1998Q2-2001Q1), a 3-quarter UCS roll-out period (2001Q2- 22 23 2001Q4; grey box in figures), and 19 quarters post-reform (2002Q1-2006Q3). We dropped 24 25 2006Q4 from the analysis since there was a policy change at this time (the removal of an initial 26 30 Baht co-payment per visit) that may have impacted outcomes. In sensitivity analyses, we 27 28 extended the intervention roll-out period through 2002 and through 2003 to account for 29 30 potentially delayed implementation and lag of actual enrollment into the scheme. 31 32 33 We used segmented linear regression to measure the pre-reform trend, the immediate level 34 http://bmjopen.bmj.com/ 35 change following the intervention period, and the post-reform change in trend (as compared to 36 37 the pre-reform trend). We controlled for serial autocorrelation using an autoregressive error 38 39 model. We retained all terms in the models, even if non-significant. We used the models to 40 20 41 estimate absolute and relative differences (with 95% confidence intervals) in observed versus 42 predicted total volume at one year and five years post-reform. In sensitivity analyses, we on September 26, 2021 by guest. Protected copyright. 43 44 included a quadratic term for the post-reform trend and used a likelihood ratio test to determine 45 46 the best-fitting model. We report below results from the best-fitting model of the shortest (i.e., 3 47 48 quarter) intervention period and mention differences in model results where they existed. Results 49 50 from sensitivity analyses are available upon request. We used the AUTOREG procedure in SAS 51 9.2 for all analyses. 52 53 54 Results 55 56 57 58 Hospital Sector Volume 59 60 8 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 52 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 The majority of sales in Thailand for all cancer, cardiovascular disease and diabetes medicines 4 5 studied were in the hospital sector and were for medicines on the NLEM. After implementation 6 7 of the UCS, there was a significant increase in level of sales of insulins and a significant increase 8 9 in trend in sales of antidiabetic, insulin, antihypertensive, lipid regulating, and cytostatic 10 11 hormone products [Table 1, Figures 1 and 2]. There was a significant reduction in level of sales 12 immediately following the reforms for three medication classes: antihypertensive, cardiac 13 14 therapy and immunostimulating agents (although only the latter was significant in the sensitivity 15 For peer review only 16 analyses using a longer intervention period). 17 18 19 The UCS was associated with increased sales of diabetes medicines. One year after the policy, 20 21 the sale of insulin was 35% (95% CI: 15%, 55%) higher and, at five years, 174% (95% CI: 22 23 114%-235%) higher than what would have been expected in the absence of the UCS [Table 2]. 24 25 The increase in insulin sales was driven primarily by human insulins, which are on the NLEM 26 and marketed as branded generics by two manufacturers. The policy was associated with a 39% 27 28 (95% CI: 14%, 64%) increase in antidiabetic product sales five years after implementation 29 30 [Table 2]. This is largely due to increased sales of generic and branded generic metformin and 31 32 glibenclamide products, both of which are on the NLEM. 33

34 http://bmjopen.bmj.com/ 35 Implementation of the UCS appears to have had a mixed impact on sales of cardiovascular 36 37 medicines. Five years after the policy, the sale of lipid lowering agents was nearly double (108% 38 39 increase; 95% CI: 60%, 157%) what would have been expected in the absence of the scheme 40 41 [Table 2]. The increase was primarily due to sales of branded generic simvastatin and 42 gemfibrozil products, which are on the NLEM, and a small but steady increase in sales of on September 26, 2021 by guest. Protected copyright. 43 44 originator atorvastatin products, which are not on the NLEM. For antihypertensives, the 45 46 significant increase in post-policy trend compensated for an initial drop in sales, resulting in a 47 48 slight increase in sales five years after the policy (19% increase; 95% CI: -3%, 40%). The 49 50 increased trend was primarily due to sales of enalapril, atenolol, and amlodipine, all of which are 51 on the NLEM and predominately sold as branded generics. The reform had no significant impact 52 53 on sales of cardiac therapy medicines one or five years after the policy. 54 55 56 57 58 59 60 9 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 52 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 The results were also mixed for cancer medicines. The UCS had no significant one- or five-year 4 5 impact on the sale of antineoplastics or cytostatic hormones (although the latter class did 6 7 experience a significant post-policy increase in trend). However, the policy was associated with 8 9 an immediate reduction in sales of immunostimulating agents that did not recover in the post- 10 11 policy period. One year after implementation, the sale of immunostimulating agents was 35% 12 (95% CI: -45%, -25%) lower than expected from pre-policy trends, and 26% lower (95% CI: - 13 14 45%, -8%) five years post-policy. This drop is almost entirely due to a sharp reduction in sales of 15 For peer review only 16 interferon alfa-2b, a non-NLEM medicine, around the time of UCS implementation, which could 17 21 18 have been due to a co-incidental recall of an interferon alfa-2b product. 19 20 21 There was mixed evidence about the effects of the UCS on utilization of NLEM medicines. For 22 23 all classes that experienced a post-policy increase in trend, there was an increase in sales of both 24 25 NLEM medicines (except for cytostatic hormones) and non-NLEM products [see online 26 appendix, Table 3]. The immediate decrease in sales of cardiac therapies and immunostimulating 27 28 agents was largely due to a decrease in non-NLEM medicines. However, for these two classes, 29 30 there was no corresponding increase in NLEM medicines. 31 32 33 Finally, as expected, the reform had little impact on sales volume in the retail sector – there were 34 http://bmjopen.bmj.com/ 35 few significant post-implementation changes, and the changes that were significant were small in 36 37 magnitude [see online appendix, Table 2]. 38 39 40 41 Hospital Sector Market Share 42 Immediately following the reform, there were significant shifts in hospital sector market share by on September 26, 2021 by guest. Protected copyright. 43 44 licensing status for most classes [Table 3]. The changes for antidiabetics and cardiac medicines - 45 46 the two therapeutic classes with the largest shifts – were due to significant increases in GPO- 47 48 produced medicines, primarily at the expense of branded generics and, to a lesser extent, 49 50 generics. There was a significant increase in GPO antidiabetic products (+16% of market; 95% 51 CI: 12%, 20%), and decreases in branded generic (-12%; 95% CI:-16%, -9%) and generic (-4%; 52 53 95% CI: -6%,-1%) products immediately after the policy [Figure 3]. Similarly, there was a 54 55 significant increase in GPO cardiac therapy products (+22%; 95% CI: 15%, 28%), and 56 57 significant decreases of branded generic (-14%; 95% CI:-21%, -7%) and generic (-4%; 95% CI:- 58 59 60 10 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 52 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 6%, -2%) products immediately after the policy [Figure 4]. There was also a small decrease in 4 5 market share of generic antihypertensives (-6%; 95% CI: -8%, -3%), which was compensated for 6 7 by a marginally significant increase in GPO products. 8 9 10 11 The market for lipid regulating agents experienced an immediate shift from originator products (- 12 8% market share; 95% CI: -10%, -5%) to branded generics (+8%; 95% CI: 5%, 10%). A similar 13 14 shift was seen for in the market for immunostimulating agents (6% decrease in originator 15 For peer review only 16 products [95% CI:-10%, -3%] and a 5% increase in branded generics [95% CI:2%, 7%]). The 17 18 cytostatic hormone market experienced an immediate shift from branded generic (-8%; 95% CI:- 19 12%, -4%) to generic products (+6%, 95% CI: 1%, 11%). Generic insulins experienced a slight 20 21 decrease in market share caused by the market exit of the sole generic manufacturer just prior to 22 23 the policy. There were no immediate changes in market share for antineoplastics. Aside from the 24 25 immediate level changes following the policy, there were few major changes in market share for 26 all classes. 27 28 29 30 Discussion 31 32 The UCS was associated with long-term (i.e., 5 year) increases in hospital sector sales of 33 medicines for chronic diseases that are usually treated in primary care settings, such as diabetes, 34 http://bmjopen.bmj.com/ 35 high blood pressure, and high cholesterol. We hypothesized this gradual increase in volume since 36 37 the UCS expanded access to primary care7 and actual enrollment into the scheme occurred 38 39 gradually from implementation in 2001 until around 2005, by which time 95·5% of the 40 7 41 population had insurance coverage. The UCS, which radically changed hospital financing and 42 reimbursement, was also associated with an immediate market shift to locally produced or on September 26, 2021 by guest. Protected copyright. 43 44 branded generic products for most therapeutic classes. 45 46 47 48 Despite these increases in access, the policy did not appear to increase sales of medicines for 49 50 more severe diseases like heart failure, arrhythmias, and cancer, which are often treated in 51 secondary or tertiary settings. This finding is in line with evidence that the capitated payment 52 53 system discouraged referrals of UCS patients to higher-level care.5,7,22 The UCS also appears to 54 55 have had a mixed impact on utilization of essential medicines. There were increases in NLEM 56 57 medicines, which are covered, as well as non-NLEM medicines. Similarly, given the capitated 58 59 60 11 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 52 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 UCS payment system, we expected to see an increase in sales of generic medicines, which are 4 5 typically less expensive. However, the majority of sales in most classes were for branded generic 6 7 products, many of which had generic alternatives in the market. Interestingly, substantial market 8 9 share shifts occurred toward products manufactured by the Thai GPO, which by law received 10 23 11 preferential status by hospital purchasers. GPO products have been noted to have higher than 12 market prices24 and sometimes to be of substandard quality.25 13 14 15 For peer review only 16 Our study demonstrates the value of IMS Health market intelligence data for rigorous health 17 18 policy evaluation. Unlike other sources of data on pharmaceutical utilization (i.e., national health 19 surveys or ad hoc hospital surveys), IMS data represent country pharmaceutical markets 20 21 consistently over time and are useful for the evaluation of system-wide interventions. 22 23 Nevertheless, the data pose some limitations. Aggregate national sales data do not allow us to 24 25 determine whether observed increases in medicines sales occurred preferentially among UCS 26 enrollees or enrollees in the SHI and CSMBS schemes, conceivably to compensate for financial 27 28 strain of the UCS on hospital budgets.5 CSMBS expenditures increased following UCS 29 30 implementation26 and increased medicines sales among CSMBS, reimbursed on a fee-for-service 31 32 basis, could explain increases in non-NLEM medicines and medicines with less expensive 33 27 therapeutic alternatives. However, it is unlikely that increased utilization among CSMBS 34 http://bmjopen.bmj.com/ 35 enrollees explains most of the observed volume changes since it would imply that one-quarter 36 37 (for diabetes) to one-third (for hypertension) of CSMBS members were on these treatments and 38 39 the change in utilization would have needed to be coincident with the initiation of the UCS. 40 41 42 Our interpretation of the observed changes assumes that pharmaceutical sales to hospital and on September 26, 2021 by guest. Protected copyright. 43 44 retail pharmacies reflected total market utilization, and that hospital sales volumes included 45 46 utilization at affiliated primary care units. This assumption seems justified in light of the 47 28 48 estimated 91% accuracy of IMS Health data in representing the Thai pharmaceutical market. 49 50 For local generic products, including those produced by the GPO, IMS Health data is based on 51 pharmacy surveys only (as opposed to pharmacy surveys and manufacturer reports), so we may 52 53 have underestimated utilization. Finally, since we did not convert standard units of product sold 54 55 to defined daily doses (DDD), we do not describe sales changes in terms of average adult doses. 56 57 58 59 60 12 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 52 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 There are also potential limitations due to study design and statistical analysis. We addressed the 4 5 main threat to the internal validity of the interrupted time series design - a concurrent event that 6 7 affects the outcome of interest - by assessing other policies or market events that occurred at the 8 9 time of the UCS, through literature reviews, discussions with in-country experts, and by 10 11 including the retail sector as a comparison. The statistical approach, segmented regression 12 analysis, usually assumes a linear trend and well-defined break point. Sensitivity analyses that 13 14 varied model specification and intervention duration did not change the findings. By reporting 15 For peer review only 16 results from fully-specified models, we may have underestimated the statistical significance of 17 18 one- and five-year change estimates. 19 20 21 While both the context and the implementation of universal coverage in Thailand are unique, our 22 23 findings suggest that expanding health insurance coverage with a medicines benefit to the entire 24 25 population in a LMIC increased the volume of medicines sold and, by inference, improved 26 access to medicines in the primary care sector. Since the study period, Thailand has enacted 27 28 further policies to address pharmaceutical sector cost escalation (e.g., strict enforcement of 29 30 reimbursement for only NLEM medicines in the CSMBS29) and to ensure appropriate access to 31 32 non-NLEM medicines (e.g., coverage of medicines for HIV, renal replacement therapy, and 33 mental health conditions).30–32 In the future, it will be important for Thailand and other countries 34 http://bmjopen.bmj.com/ 35 to assess quality of medicines use, out-of-pocket and system expenditures, and health outcomes 36 37 as they pursue policies to achieve universal coverage. 38 39 40 41 42 on September 26, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 13 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 52 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 References 4 5 1 World Health Organization. Resolution from the fifty-eight World Health Assembly. 6 7 Sustainable health financing, universal coverage and social health insurance (WHA58.33) 8 [Internet]. 2005 [cited 2011 Mar 8]. Available from: 9 http://www.who.int/providingforhealth/topics/WHA58_33-en.pdf. 10 11 2 World Health Organization. 2010 World Health Report: Health systems financing: the 12 13 path to universal coverage [Internet]. 2010 [cited 2011 Mar 8]. Available from: 14 http://www.who.int/whr/2010/en/index.html. 15 For peer review only 16 3 J. Quick, Ensuring access to essential medicines in developing countries—A framework 17 for action. Clinical Pharmacology and Therapeutics 2003; 73(4): 279–283. 18 19 20 4 Faden L, Vialle-Valentin C, Ross-Degnan D, Wagner A. Active pharmaceutical 21 management strategies of health insurance systems to improve cost-effective use of 22 medicines in low- and middle-income countries: a systematic review of current evidence. 23 Health Policy. 2011; 100(2-3): 134-143. 24 25 26 5 Hughes D, Leethongdee S. Universal coverage in the land of smiles: lessons from 27 Thailand's 30 Baht health reforms. Health Aff (Millwood). 2007; 26(4): 999-1008. 28 29 6 The Rockefeller Foundation. Catalyzing Change: The System Reform Costs of Universal 30 Health Coverage [Internet]. 2010 Nov 15 [cited on 2011 Mar 8]. Available from: 31 32 http://www.rockefellerfoundation.org/news/publications/catalyzing-change-system- 33 reform-costs.

34 http://bmjopen.bmj.com/ 35 7 Damrongplasit K, Melnick GA. Early results from Thailand's 30 Baht Health Reform: 36 something to smile about. Health Aff (Millwood). 2009; 28(3): w457-466. 37 38 39 8 Tangcharoensathien V, Wibulpholprasert S, Nitayaramphong S. Knowledge-based 40 changes to health systems: the Thai experience in policy development. Bull. World 41 Health Organ. 2004; 82(10): 750-756. 42 on September 26, 2021 by guest. Protected copyright. 43 9 NaRanong V, NaRanong, A, Treamworakul S. Universal Health Coverage Schemes in 44 45 Thailand 2002-2003. Research Report No.1: Monitoring and Evaluating Universal Health 46 Care Coverage in Thailand, Phase II, 2003-04. Bangkok: Thailand Development 47 Research Institute; 2004. 48 49 10 Kaufman N, Chasombat S, Tanomsingh S, Rajataramya B, Potempa K. Public health in 50 Thailand: emerging focus on non-communicable diseases. Int J Health Plann Manage. 51 52 2011; 26(3): e197-212 53 54 11 Bundhamcharoen K, Odton P, Phulkerd S, Tangcharoensathien V. Burden of disease in 55 Thailand: changes in health gap between 1999 and 2004. BMC Public Health. 2011;11: 56 53. 57 58 59 60 14 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 52 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 12 World Health Organization. Thailand: Health Profile [Internet]. 2011 Apr 11 [cited 2012 4 5 Feb 8]. Available from: http://www.who.int/gho/countries/tha.pdf 6 7 13 Porapakkham Y, Rao C, Pattaraarchachai J, et al. Estimated causes of death in Thailand, 8 2005: implications for health policy. Population Health Metrics. 2010; 8(1): 14. 9 10 11 14 Beaglehole R, Bonita R, Horton R, et al. Priority actions for the non-communicable 12 disease crisis. Lancet. 2011; 377(9775): 1438-1447. 13 14 15 IMS Health MIDAS. 1998-2006. 15 For peer review only 16 16 European Pharmaceutical Market Research Association (EphMRA). Anatomical 17 18 Classification [Internet]. 2012 [cited 2012 Feb 6]. Available from: 19 http://www.ephmra.org/classification/anatomical-classification.aspx 20 21 17 The World Bank. Data [Internet]. 2011 [cited 2011 May13]. Availalble from: 22 http://data.worldbank.org/ 23 24 25 18 Wagner AK, Soumerai SB, Zhang F, Ross-Degnan D. Segmented regression analysis of 26 interrupted time series studies in medication use research. J Clin Pharm Ther. 2002; 27 27(4): 299-309. 28 29 19 Shadish WR, Cook TD, Campbell DT. Experimental and quasi-experimental designs for 30 31 generalized causal inference. Boston: Houghton Mifflin Company; 2002. 32 33 20 Zhang F, Wagner AK, Soumerai SB, Ross-Degnan D. Methods for estimating confidence

34 intervals in interrupted time series analyses of health interventions. J Clin Epidemiol. http://bmjopen.bmj.com/ 35 2009; 62(2): 143-148. 36 37 38 21 United States. Food and Drug Agency. Recall of Interferon alfa-2b, (Recombinant), 39 Powder for Injection, Intron A - (Schering Corporation) [Internet]. 2001 Oct 22 [cited 13 40 Oct 2011]. Available from: 41 http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandAp 42 on September 26, 2021 by guest. Protected copyright. 43 proved/ApprovalApplications/TherapeuticBiologicApplications/ucm113617.htm 44 45 22 Yiengprugsawan V, Carmichael G, Lim L, Seubsman S, Sleigh A. Explanation of 46 inequality in utilization of ambulatory care before and after universal health insurance in 47 Thailand. Health Policy Plan. 2011; 26(2): 105-14. 48 49 50 23 Ratanawijitrasin S. Pharmaceutical policy in Thailand: a review of three decades of 51 government interventions. In: Eggleston K, editor. Prescribing cultures and 52 pharmaceutical policy in the Asia Pacific. Stanford: The Walter H. Shorenstein Asia- 53 Pacific Research Center Books; 2009. p. 79–106. 54 55 56 24 Ten Kate D. Safe at any costs? Asia Sentinel (Hong Kong) [Internet]. 2001 Jan 4 [cited 57 2012 Feb 6]. Available from: 58 59 60 15 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 52 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 http://www.asiasentinel.com/index.php?option=com_content&task=view&id=351&Itemi 4 5 d=392 6 7 25 Bates, R. Local pharmaceutical production in developing countries: How economic 8 protectionism undermines access to quality medicines. Campaign for Fighting Diseases 9 discussion paper no. 1 [Internet]. 2008 Jan [cited Feb 7 2012]. Available from: 10 11 http://www.policynetwork.net/sites/default/files/local_drug_production.pdf . 12 13 26 Tangcharoensathien V, Jongudomsuk P. From policy to implementation: Historical 14 events during 2001-2011 of universal coverage in Thailand. Bangkok, Thailand: 15 National ForHealth Security peer Office; 2012. review only 16 17 18 27 Hirunrassamee S, Ratanawijitrasin S. Does your health care depend on how your insurer 19 pays providers? Variation in utilization and outcomes in Thailand. Int J Health Care 20 Finance Econ. 2009; 9(2): 153-168. 21 22 28 IMS Health. IMS Thailand Market Prognosis. 2012. 23 24 25 29 IMS Health. Pharma Pricing and Reimbursement. 2011 Mar; 16(3). 26 27 30 Khanna R. Universal Health Coverage in Thailand: What Lessons Can India Learn? 28 [Internet]. 2010 Dec 16 [cited 2012 Feb 7]. Available from: 29 http://www.mfcindia.org/main/bgpapers/bgpapers2011/am/bgpap2011r.pdf 30 31 32 33 31 Treerutkuarkul A. Thailand: health care for all, at a price. Bull World Health Organ.

34 2010; 88(2): 84-5. http://bmjopen.bmj.com/ 35 36 32 Pitayarangsarit S. The Introduction of the Universal Coverage of Health Care Policy in 37 Thailand: Policy Responses [PhD thesis]. London, UK: London School of Hygiene and 38 39 Tropical Medicine; 2004 [cited 2012 Feb 7]. Available from: 40 http://www.nhso.go.th/eng/download/The%20Introduction%20of%20the%20Universal% 41 20Coverage%20of%20Health%20Care%20Policy%20in%20Thailand_%20Policy%20Re 42 sponses.pdf on September 26, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 16 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 52 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 TABLES 4 5 6 Table 1. Summary of the Impact of the Universal Coverage Scheme on Volume in the Hospital 7 Sector (from segmented regression results) * 8 Therapeutic Area Pre-policy trend Immediate change after Post-policy trend change 9 policy 10

11 12 DIABETES 13 Antidiabetics** 14 Insulins** 15 For peer review only 16 17 CARDIOVASCULAR DISEASE 18 19 Antihypertensives 20 Lipid Regulating Agents** 21 Cardiac Therapy 22 23 24 CANCER 25 Antineoplastics 26 27 Cytostatic Hormones 28 Immunostimulating Agents** 29 *Arrows signify a statistically significant coefficient (p<0.05) from segmented regression with linear post-policy trend term, unless noted otherwise. 30 **Quadratic model (which has a squared post-policy trend term) fits better than linear model. 31 Note: See online appendix Table 2 and Figures 1-8 for regression coefficients and figures for all therapeutic areas. 32 33

34 http://bmjopen.bmj.com/ 35 Table 2. Relative Impact of UCS on Sales of Medicines by Class (one and five years post policy)* 36 Therapeutic Class One Year Impact (in standard units) Five Year Impact (in standard units) 37 Predicted Observed Relative Change Predicted Observed Relative Change 38 (95% CI) (95% CI) 39 Antidiabetics 2602·91 2769·79 6·4% (-6·9, 19·7) 3669·13 5090·62 38·7% (13·5, 64·0) 40 41 Insulins 3·30 4·45 34·8% (15·1, 54·5) 4·58 12·56 174·4% (113·9, 235·0) 42 Cardiac Therapy Agents 607·27 -13·2% (-26·9, 0·6) 908·12 825·49 -9·1% (-31·9, 13·1) 699·28 on September 26, 2021 by guest. Protected copyright. 43 Lipid Regulating Agents 522·34 504·58 -3·4% (-19·9, 13·1) 781·97 1629·11 108·3% (59·8, 156·9) 44 45 Antihypertensives 3521·47 3418·79 -2·9% (-15·5, 9·7) 5200·86 6177·49 18·8% (-2·8, 40·3)** 46 Antineoplastics 35·38 34·21 -3·3% (-15·4, 8·7) 46·14 48·13 4·3% (-16·3, 24·9) 47 48 Cytostatic Hormones 29·48 30·58 3·7% (-10·1, 17·6) 39·82 47·52 19·3% (-5·1, 43·8) 49 Immunostimulating 0·65 0·43 -35·0% (-45·1, -25·0) 0·81 0·60 -26·3% (-45·0, -7·6) 50 Agents 51 *Bold signifies that the change is statistically significant (i.e., confidence interval does not include the null value of 0). 52 ** The absolute five-year difference, which is estimated using more precise method, is significant. See online appendix Table 4. 53 54 55 56 57 58 59 60 17 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18 of 52 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 Table 3. Immediate Impact of UCS on Hospital Sector Market Share* 4 5 Therapeutic Area Licensing Status Immediate post-policy 6 absolute change 7 in % market share (95% CI) 8 DIABETES 9 Antidiabetics Originator brand -0·3% (-1·6, 1·0) 10 Branded generic -12·3% (-16·0, -8·7) 11 Generic -3·5% (-5·8, -1·1) 12 13 GPO 16·1% (12·0, 20·2) 14 Insulins*** Originator brand** -0·04% (-0·4, 0·3) 15 For Branded peer generic review7·0% (2·9, 11only·1) 16 Generic -6·2% (-10·3, -2·1) 17 18 CARDIOVASCULAR DISEASE 19 20 Antihypertensives Originator brand** -0·1% (-2·3, 2·0) 21 Branded generic** -0·2% (-6·1, 1·8) 22 Generic -5·7% (-8·3, -3·0) 23 GPO 5·3% (-0·1, 10·6) 24 25 Lipid Regulating Originator brand** -7·8% (-10·2, -5·4) 26 Agents 27 Branded generic** 7·6% (5·1, 10·0) 28 Generic 0·2% (-0·4, 0·7) 29 GPO 0·2% (-0·3, 0·8) 30 Cardiac Therapy Originator brand 0·1% (-0·8, 1·0) 31 32 Branded generic** -13·5% (-20·5, -6·5) 33 Generic -4·3% (-6·2, -2·4)

34 GPO 21·6% (15·0, 28·1) http://bmjopen.bmj.com/ 35 CANCER*** 36 37 Antineoplastics Originator brand 1·1% (-1·0, 3·2) 38 Branded generic -1·0% (-5·4, 3·4) 39 Generic 0·4% (-2·7, 3·4) 40 Cytostatic Hormones Originator brand** 0·4% (-5·4, 6·1) 41 42 Branded generic** -7·7% (-12·0, -3·5) on September 26, 2021 by guest. Protected copyright. 43 Generic** 6·0% (1·4, 10·6) 44 Immunostimulating Originator brand -6·4% (-9·7, -3·0) 45 Agents 46 Branded generic 4·5% (1·7, 7·3) 47 Generic -0·2% (-0·3, 0·02) 48 49 *Bold signifies a statistically significant regression coefficient (p<0.05). Changes are in absolute terms (i.e., percentage point change). **Quadratic model (which has a squared post-policy term) fits better than linear model. 50 ***GPO did not produce any insulins or cancer medicines during the study period. 51 Note 1: See online appendix Table 5 and Figures 9-16 for market share regression coefficients and figures for all therapeutic areas 52 Note 2: Aside from the immediate level changes following the policy, there were few major changes in market share. See online appendix, Table 53 6 for absolute one- and five-year differences. 54 55 56 57 58 59 60 18 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 52 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 Figure Index (attached in separate document):* 4 5 Figure 1. Standard Units Per Capita by Quarter: Insulin (Hospital vs. Retail) 6 7 Figure 2. Standard Units Per Capita by Quarter: Antihypertensives (Hospital vs. Retail) 8 9 Figure 3. Licensing Status Market Share by Quarter: Antidiabetics (Hospital Sector) 10 11 12 Figure 4. Licensing Status Market Share by Quarter: Cardiac Therapy Products (Hospital 13 Sector) 14 15 *The grey box inFor each figure peer represents the review 3-quarter UCS roll-out only period. 16 17 18 Online appendix (attached in separate document) 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33

34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on September 26, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 19 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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1 2 3 Figure 1. Total Volume (Standard Units Per Capita) by Quarter 4 5 for Insulin (Hospital vs. Retail Pharmacies) 6 7 14 8 9 10 11 12 For peer review only 12 13

14 15 10 16 17 18 19 http://bmjopen.bmj.com/ 20 8 21 22 Hospital Insulin 23 Retail Insulin 24 6 * 25 Hospital Regression Line 26 Retail Regression Line

27 on September 26, 2021 by guest. Protected copyright. 28 Predicted Hospital Regression Line 29 4 30 Number Standardof Units per 1000people 31 32 33 2 34 35 36 37 0 38 39 40 41 1998Q2 1998Q3 1998Q4 1999Q1 1999Q2 1999Q3 1999Q4 2000Q1 2000Q2 2000Q3 2000Q4 2001Q1 2001Q2 2001Q3 2001Q4 2002Q1 2002Q2 2002Q3 2002Q4 2003Q1 2003Q2 2003Q3 2003Q4 2004Q1 2004Q2 2004Q3 2004Q4 2005Q1 2005Q2 2005Q3 2005Q4 2006Q1 2006Q2 2006Q3 Quarter 42 43 *Results from quadratic model 44 45 46 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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1 2 3 Figure 2. Total Volume (Standard Units Per Capita) by Quarter 4 5 for Antihypertensives (Hospital vs. Retail Pharmacies) 6 7000 7 8 9 10 11 6000 For peer review only 12 13

14 15 5000 16 17 18 19 http://bmjopen.bmj.com/ 20 4000 21 22 Hospitial Antihypertensives 23 Retail Antihypertensives 24 3000 25 Hosptial Regression Line 26 Retail Regression Line

27 on September 26, 2021 by guest. Protected copyright. Predicted Hospital Regression Line 28 29 2000

30 Number Standardof Units per 1000people 31 32 33 1000 34 35 36 37 38 0 39 40

41 1998Q2 1998Q3 1998Q4 1999Q1 1999Q2 1999Q3 1999Q4 2000Q1 2000Q2 2000Q3 2000Q4 2001Q1 2001Q2 2001Q3 2001Q4 2002Q1 2002Q2 2002Q3 2002Q4 2003Q1 2003Q2 2003Q3 2003Q4 2004Q1 2004Q2 2004Q3 2004Q4 2005Q1 2005Q2 2005Q3 2005Q4 2006Q1 2006Q2 2006Q3 42 Quarter 43 44 45 46 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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1 2 3 Figure 3. Licensing Status Market Share by Quarter 4 5 for Antidiabetics (Hospital Pharmacies) 6 0.7 7 8 9 10 11 0.6 For peer review only 12 13 14 15 0.5 16 17 18 19 http://bmjopen.bmj.com/ Originator brand 20 0.4 21 Branded generic 22 Generic 23 24 GPO 0.3 25 Originator brand line 26

27 on September 26, 2021 by guest. Protected copyright. Branded generic line 28 Generic line 29 0.2 30 ShareMarket (% ofstandard total units) GPO line 31 32 33 0.1 34 35 36 37 38 0 39 40

41 1998Q2 1998Q3 1998Q4 1999Q1 1999Q2 1999Q3 1999Q4 2000Q1 2000Q2 2000Q3 2000Q4 2001Q1 2001Q2 2001Q3 2001Q4 2002Q1 2002Q2 2002Q3 2002Q4 2003Q1 2003Q2 2003Q3 2003Q4 2004Q1 2004Q2 2004Q3 2004Q4 2005Q1 2005Q2 2005Q3 2005Q4 2006Q1 2006Q2 2006Q3 42 Quarter 43 44 45 46 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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1 2 3 Figure 4. Licensing Status Market Share by Quarter 4 5 for Cardiac Therapy Agents (Hospital Pharmacies) 6 0.9 7 8 9 10 0.8 11 For peer review only 12 13 0.7 14 15 16 17 0.6 18 19 http://bmjopen.bmj.com/ Originator brand 20 0.5 21 Branded generic 22 Generic 23 24 0.4 GPO 25 Originator brand line 26

27 on September 26, 2021 by guest. Protected copyright. Branded generic line* 0.3 28 Generic line 29 30 ShareMarket (% ofstandard total units) GPO line 31 0.2 32 33 34 0.1 35 36 37 38 0 39 40

41 1998Q2 1998Q3 1998Q4 1999Q1 1999Q2 1999Q3 1999Q4 2000Q1 2000Q2 2000Q3 2000Q4 2001Q1 2001Q2 2001Q3 2001Q4 2002Q1 2002Q2 2002Q3 2002Q4 2003Q1 2003Q2 2003Q3 2003Q4 2004Q1 2004Q2 2004Q3 2004Q4 2005Q1 2005Q2 2005Q3 2005Q4 2006Q1 2006Q2 2006Q3 42 Quarter 43 *Results from quadratic model 44 45 46 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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Appendix Table 1. List of Medicines by ATC 1 NLEM (1=on NLEM Therapeutic Area Classification for Analysis Molecule Name ATC2 Classification ATC4 Classification Note regarding NLEM 2 1999-2004) DIABETES 3 Antidiabetics ACARBOSE A10 (DRUGS USED IN DIABETES) A10L0 (A-GLUCOSIDASE INH A-DIAB) 1 4 Antidiabetics BUFORMIN A10 (DRUGS USED IN DIABETES) A10J1 (BIGUANIDE A-DIABS PLAIN) 0 Antidiabetics CHLORPROPAMIDE A10 (DRUGS USED IN DIABETES) A10H0 (SULPHONYLUREA A-DIABS) 1 5 Antidiabetics EXENATIDE A10 (DRUGS USED IN DIABETES) A10S0 (GLP-1 AGONIST A-DIABS) 0 6 Antidiabetics GLIBENCLAMIDE A10 (DRUGS USED IN DIABETES) A10H0 (SULPHONYLUREA A-DIABS ) 1 Antidiabetics GLIBENCLAMIDE#METFORMIN A10 (DRUGS USED IN DIABETES) A10J2 (BIGUANIDE & S-UREA COMBS) 0 both ingredients listed separately, not in combo 7 Antidiabetics GLICLAZIDE A10 (DRUGS USED IN DIABETES) A10H0 (SULPHONYLUREA A-DIABS) 1 8 Antidiabetics GLICLAZIDE#METFORMIN A10 (DRUGS USED IN DIABETES) A10J2 (BIGUANIDE & S-UREA COMBS) 0 both ingredients listed separately, not in combo Antidiabetics GLIMEPIRIDE A10 (DRUGS USED IN DIABETES) A10H0 (SULPHONYLUREA A-DIABS) 0 9 Antidiabetics GLIMEPIRIDE#METFORMIN A10 (DRUGS USED IN DIABETES) A10J2 (BIGUANIDE & S-UREA COMBS) 0 10 Antidiabetics GLIMEPIRIDE#ROSIGLITAZONE A10 (DRUGS USED IN DIABETES) A10K2 (GLITAZONE & S-UREA COMBS) 0 11 Antidiabetics GLIPIZIDE A10 (DRUGS USED IN DIABETES) A10H0 (SULPHONYLUREA A-DIABS) 1 Antidiabetics GLIQUIDONEFor peer A10review (DRUGS USED IN DIABETES) A10H0 (SULPHONYLUREA only A-DIABS) 0 12 Antidiabetics METFORMIN A10 (DRUGS USED IN DIABETES) A10J1 (BIGUANIDE A-DIABS PLAIN) 1 Antidiabetics METFORMIN#PIOGLITAZONE A10 (DRUGS USED IN DIABETES) A10K3 (GLITAZONE & BIGUAN COMBS) 0 13 Antidiabetics METFORMIN#ROSIGLITAZONE A10 (DRUGS USED IN DIABETES) A10K3 (GLITAZONE & BIGUAN COMBS) 0 14 Antidiabetics METFORMIN#SITAGLIPTIN A10 (DRUGS USED IN DIABETES) A10N3 (DPP-IV INH & BIGUAN COMB) 0 Antidiabetics METFORMIN#VILDAGLIPTIN A10 (DRUGS USED IN DIABETES) A10N3 (DPP-IV INH & BIGUAN COMB) 0 15 Antidiabetics PIOGLITAZONE A10 (DRUGS USED IN DIABETES) A10K1 (GLITAZONE A-DIABS PLAIN) 0 16 Antidiabetics REPAGLINIDE A10 (DRUGS USED IN DIABETES) A10M1 (GLINIDE A-DIABS PLAIN) 0 Antidiabetics ROSIGLITAZONE A10 (DRUGS USED IN DIABETES) A10K1 (GLITAZONE A-DIABS PLAIN) 0 17 Antidiabetics SITAGLIPTIN A10 (DRUGS USED IN DIABETES) A10N1 (DPP-IV INH A-DIAB PLAIN) 0 18 Antidiabetics VILDAGLIPTIN A10 (DRUGS USED IN DIABETES) A10N1 (DPP-IV INH A-DIAB PLAIN) 0 19 Antidiabetics VOGLIBOSE A10 (DRUGS USED IN DIABETES) A10L0 (A-GLUCOSIDASE INH A-DIAB) http://bmjopen.bmj.com/ 0 Insulins INSULIN ASPART A10 (DRUGS USED IN DIABETES) A10C1 (H INSUL+ANG FAST ACT) 1 according to pesonal communication, all insulins are on NLEM 20 Insulins INSULIN ASPART#INSULIN ASPART PROTAMINE CRYSTALLINE A10 (DRUGS USED IN DIABETES) A10C3 (H INSUL+ANG INT+FAST ACT) 1 according to pesonal communication, all insulins are on NLEM 21 Insulins INSULIN DETEMIR A10 (DRUGS USED IN DIABETES) A10C5 (H INSUL+ANG LONG ACT) 1 according to pesonal communication, all insulins are on NLEM Insulins INSULIN GLARGINE A10 (DRUGS USED IN DIABETES) A10C5 (H INSUL+ANG LONG ACT) 1 according to pesonal communication, all insulins are on NLEM 22 Insulins INSULIN HUMAN BASE A10 (DRUGS USED IN DIABETES) A10C1 (H INSUL+ANG FAST ACT) 1 according to pesonal communication, all insulins are on NLEM 23 Insulins INSULIN HUMAN BASE#INSULIN HUMAN ISOPHANE A10 (DRUGS USED IN DIABETES) A10C3 (H INSUL+ANG INT+FAST ACT) 1 according to pesonal communication, all insulins are on NLEM Insulins INSULIN HUMAN ISOPHANE A10 (DRUGS USED IN DIABETES) A10C2 (H INSUL+ANG INTERMED ACT) 1 according to pesonal communication, all insulins are on NLEM 24 Insulins INSULIN HUMAN ZINC SUSPENSION (COMPOUND) A10 (DRUGS USED IN DIABETES) A10C4 (H INSUL+ANG INT+LONG ACT) 1 according to pesonal communication, all insulins are on NLEM 25 Insulins INSULIN HUMAN ZINC SUSPENSION (CRYSTALLINE) A10 (DRUGS USED IN DIABETES) A10C5 (H INSUL+ANG LONG ACT) 1 according to pesonal communication, all insulins are on NLEM Insulins INSULIN LISPRO A10 (DRUGS USED IN DIABETES) A10C1 (H INSUL+ANG FAST ACT) 1 according to pesonal communication, all insulins are on NLEM 26 Insulins INSULIN LISPRO#INSULIN LISPRO PROTAMINE A10 (DRUGS USED IN DIABETES) A10C1 (H INSUL+ANG FAST ACT ) 1 according to pesonal communication, all insulins are on NLEM Insulins INSULIN PORCINE BASE A10 (DRUGS USED IN DIABETES) A10D0 (ANIMAL INSULINS) 1 according to pesonal communication, all insulins are on NLEM 27 on September 26, 2021 by guest. Protected copyright. Insulins INSULIN PORCINE ISOPHANE A10 (DRUGS USED IN DIABETES) A10D0 (ANIMAL INSULINS) 1 according to pesonal communication, all insulins are on NLEM 28 Insulins INSULIN PORCINE ZINC SUSPENSION (COMPOUND) A10 (DRUGS USED IN DIABETES) A10D0 (ANIMAL INSULINS ) 1 according to pesonal communication, all insulins are on NLEM 29 CARIOVASCULAR DISEASE 30 Antihypertensives AJMALICINE#BUTIZIDE#RESCINNAMINE#RESERPINE C2 (ANTIHYPERTENSIVES) C2D0 (RAUWOLF ALK+OTH COM+DIUR) 0 31 Antihypertensives BUNAZOSIN C2 (ANTIHYPERTENSIVES) C2A2 (ANTIHYPER.PL MAINLY PERI) 0 Antihypertensives CLONIDINE C2 (ANTIHYPERTENSIVES) C2A1 (ANTIHYPER.PL MAINLY CENT) 1 32 Antihypertensives CLOPAMIDE#DIHYDROERGOCRISTINE#RESERPINE C2 (ANTIHYPERTENSIVES) C2D0 (RAUWOLF ALK+OTH COM+DIUR) 0 33 Antihypertensives CLOPAMIDE#RESERPINE C2 (ANTIHYPERTENSIVES) C2D0 (RAUWOLF ALK+OTH COM+DIUR) 0 Antihypertensives DIHYDRALAZINE C2 (ANTIHYPERTENSIVES) C2A2 (ANTIHYPER.PL MAINLY PERI) 1 34 Antihypertensives DOXAZOSIN C2 (ANTIHYPERTENSIVES) C2A2 (ANTIHYPER.PL MAINLY PERI) 1 35 Antihypertensives HYDRALAZINE C2 (ANTIHYPERTENSIVES) C2A2 (ANTIHYPER.PL MAINLY PERI) 1 Antihypertensives HYDRALAZINE#HYDROCHLOROTHIAZIDE#RESERPINE C2 (ANTIHYPERTENSIVES) C2B2 (A-HYPERT(N V)MAINLY PERI) 0 all ingredients listed separately, not in combo 36 Antihypertensives KETANSERIN C2 (ANTIHYPERTENSIVES) C2A2 (ANTIHYPER.PL MAINLY PERI) 0 37 Antihypertensives METHYLDOPA C2 (ANTIHYPERTENSIVES) C2A1 (ANTIHYPER.PL MAINLY CENT) 1 Antihypertensives MINOXIDIL C2 (ANTIHYPERTENSIVES) C2A2 (ANTIHYPER.PL MAINLY PERI) 1 38 Antihypertensives NITROPRUSSIDE C2 (ANTIHYPERTENSIVES) C2A2 (ANTIHYPER.PL MAINLY PERI) 1 39 Antihypertensives PRAZOSIN C2 (ANTIHYPERTENSIVES) C2A2 (ANTIHYPER.PL MAINLY PERI) 1 Antihypertensives RESERPINE C2 (ANTIHYPERTENSIVES) C2C0 (RAUWLF ALK+OTH A-HY HERB) 1 40 Antihypertensives RILMENIDINE C2 (ANTIHYPERTENSIVES) C2A1 (ANTIHYPER.PL MAINLY CENT) 0 41 Antihypertensives 1-PROPANOL C7 (BETA BLOCKING AGENTS) C7A0 (B-BLOCKING AGENTS,PLAIN) 0 Antihypertensives AMILORIDE#HYDROCHLOROTHIAZIDE#TIMOLOL C7 (BETA BLOCKING AGENTS) C7B1 (B-BLOCK COMB HYPOT/DIURT) 1 42 Antihypertensives ATENOLOL C7 (BETA BLOCKING AGENTS) C7A0 (B-BLOCKING AGENTS,PLAIN) 1 43 Antihypertensives ATENOLOL#CHLORTALIDONE C7 (BETA BLOCKING AGENTS) C7B1 (B-BLOCK COMB HYPOT/DIURT) 0 Antihypertensives BETAXOLOL C7 (BETA BLOCKING AGENTS) C7A0 (B-BLOCKING AGENTS,PLAIN) 1 44 Antihypertensives BISOPROLOL C7 (BETA BLOCKING AGENTS) C7A0 (B-BLOCKING AGENTS,PLAIN) 0 45 Antihypertensives BISOPROLOL#HYDROCHLOROTHIAZIDE C7 (BETA BLOCKING AGENTS) C7B1 (B-BLOCK COMB HYPOT/DIURT) 0 Antihypertensives CARVEDILOL C7 (BETA BLOCKING AGENTS) C7A0 (B-BLOCKING AGENTS,PLAIN) 0 46 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. 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Antihypertensives CLOPAMIDE#PINDOLOL C7 (BETA BLOCKING AGENTS) C7B1 (B-BLOCK COMB HYPOT/DIURT) 0 1 Antihypertensives LABETALOL C7 (BETA BLOCKING AGENTS) C7A0 (B-BLOCKING AGENTS,PLAIN) 0 Antihypertensives METOPROLOL C7 (BETA BLOCKING AGENTS) C7A0 (B-BLOCKING AGENTS,PLAIN) 0 2 Antihypertensives NEBIVOLOL C7 (BETA BLOCKING AGENTS) C7A0 (B-BLOCKING AGENTS,PLAIN ) 0 3 Antihypertensives OXPRENOLOL C7 (BETA BLOCKING AGENTS) C7A0 (B-BLOCKING AGENTS,PLAIN ) 0 Antihypertensives PINDOLOL C7 (BETA BLOCKING AGENTS) C7A0 (B-BLOCKING AGENTS,PLAIN ) 0 4 Antihypertensives PROPRANOLOL C7 (BETA BLOCKING AGENTS) C7A0 (B-BLOCKING AGENTS,PLAIN ) 1 5 Antihypertensives SOTALOL C7 (BETA BLOCKING AGENTS C7A0 ) (B-BLOCKING AGENTS,PLAIN ) 0 Antihypertensives AMLODIPINE C8 (CALCIUM ANTAGONISTS) C8A0 (CALCIUM ANTAGONIST PLAIN) 1 6 Antihypertensives ATENOLOL#NIFEDIPINE C8 (CALCIUM ANTAGONISTS) C8B2 (CALC ANTAG/B BLOCKR COMB) 0 both ingredients listed separately, not in combo 7 Antihypertensives BARNIDIPINE C8 (CALCIUM ANTAGONISTS) C8A0 (CALCIUM ANTAGONIST PLAIN) 0 Antihypertensives DILTIAZEM C8 (CALCIUM ANTAGONISTS) C8A0 (CALCIUM ANTAGONIST PLAIN) 1 8 Antihypertensives FELODIPINE C8 (CALCIUM ANTAGONISTS) C8A0 (CALCIUM ANTAGONIST PLAIN) 1 9 Antihypertensives GALLOPAMIL C8 (CALCIUM ANTAGONISTS) C8A0 (CALCIUM ANTAGONIST PLAIN) 0 Antihypertensives ISRADIPINE C8 (CALCIUM ANTAGONISTS) C8A0 (CALCIUM ANTAGONIST PLAIN) 0 10 Antihypertensives LACIDIPINE C8 (CALCIUM ANTAGONISTS) C8A0 (CALCIUM ANTAGONIST PLAIN) 0 11 Antihypertensives LERCANIDIPINE C8 (CALCIUM ANTAGONISTS) C8A0 (CALCIUM ANTAGONIST PLAIN) 0 Antihypertensives MANIDIPINEFor peer C8 review(CALCIUM ANTAGONISTS) C8A0 (CALCIUM only ANTAGONIST PLAIN) 0 12 Antihypertensives MIBEFRADIL C8 (CALCIUM ANTAGONISTS) C8A0 (CALCIUM ANTAGONIST PLAIN) 0 13 Antihypertensives NICARDIPINE C8 (CALCIUM ANTAGONISTS) C8A0 (CALCIUM ANTAGONIST PLAIN) 1 Antihypertensives NIFEDIPINE C8 (CALCIUM ANTAGONISTS) C8A0 (CALCIUM ANTAGONIST PLAIN) 1 14 Antihypertensives NISOLDIPINE C8 (CALCIUM ANTAGONISTS) C8A0 (CALCIUM ANTAGONIST PLAIN) 0 15 Antihypertensives NITRENDIPINE C8 (CALCIUM ANTAGONISTS) C8A0 (CALCIUM ANTAGONIST PLAIN) 0 Antihypertensives VERAPAMIL C8 (CALCIUM ANTAGONISTS) C8A0 (CALCIUM ANTAGONIST PLAIN) 1 16 Antihypertensives AMILORIDE C3 (DIURETICS) C3A1 (POT SPARING AGENTS PLAIN) 0 17 Antihypertensives AMILORIDE#HYDROCHLOROTHIAZIDE C3 (DIURETICS) C3A5 (POT SPARING+THIAZ COMBS ) 1 Antihypertensives BAROSMA BETULINA#CAPSICUM#METHYLENE BLUE#URGINEA SCILLAC3 (DIURETICS) C3A6 (OTHER DIURETICS) 0 18 Antihypertensives BAROSMA BETULINA#HYOSCYAMUS ALBUS#POTASSIUM C3 (DIURETICS) C3A6 (OTHER DIURETICS) 0 19 Antihypertensives BENDROFLUMETHIAZIDE#POTASSIUM C3 (DIURETICS) C3A3 (THIAZIDE+ANALOGUE PLAIN) http://bmjopen.bmj.com/ 0 Antihypertensives BUMETANIDE C3 (DIURETICS) C3A2 (LOOP DIURETICS PLAIN) 0 20 Antihypertensives FUROSEMIDE C3 (DIURETICS) C3A2 (LOOP DIURETICS PLAIN) 1 21 Antihypertensives HYDROCHLOROTHIAZIDE C3 (DIURETICS) C3A3 (THIAZIDE+ANALOGUE PLAIN) 1 Antihypertensives HYDROCHLOROTHIAZIDE#TRIAMTERENE C3 (DIURETICS) C3A5 (POT SPARING+THIAZ COMBS) 0 22 Antihypertensives INDAPAMIDE C3 (DIURETICS) C3A3 (THIAZIDE+ANALOGUE PLAIN) 0 23 Antihypertensives SPIRONOLACTONE C3 (DIURETICS) C3A1 (POT SPARING AGENTS PLAIN) 1 Antihypertensives TORASEMIDE C3 (DIURETICS) C3A2 (LOOP DIURETICS PLAIN) 0 24 Antihypertensives TRIPAMIDE C3 (DIURETICS) C3A3 (THIAZIDE+ANALOGUE PLAIN) 0 25 Antihypertensives XIPAMIDE C3 (DIURETICS) C3A3 (THIAZIDE+ANALOGUE PLAIN) 0 Antihypertensives ALISKIREN C9 (RENIN-ANGIOTEN SYS AGENT) C9X0 (OTH RENIN-ANGIOTEN AGENT) 0 26 Antihypertensives ALISKIREN#HYDROCHLOROTHIAZIDE C9 (RENIN-ANGIOTEN SYS AGENT) C9X0 (OTH RENIN-ANGIOTEN AGENT) 0

27 Antihypertensives AMLODIPINE#VALSARTAN C9 (RENIN-ANGIOTEN SYS AGENT) C9D3 (AT2 ANTG COMB CALC ANTAG) on September 26, 2021 by guest. Protected copyright. 0 Antihypertensives CANDESARTAN CILEXETIL C9 (RENIN-ANGIOTEN SYS AGENT) C9C0 (ANGIOTEN-II ANTAG, PLAIN) 0 28 Antihypertensives CANDESARTAN CILEXETIL#HYDROCHLOROTHIAZIDE C9 (RENIN-ANGIOTEN SYS AGENT) C9D1 (AT2 ANTG COMB C2 &/O DIU) 0 29 Antihypertensives CAPTOPRIL C9 (RENIN-ANGIOTEN SYS AGENT) C9A0 (ACE INHIBITORS PLAIN) 1 Antihypertensives CILAZAPRIL C9 (RENIN-ANGIOTEN SYS AGENT) C9A0 (ACE INHIBITORS PLAIN) 0 30 Antihypertensives DELAPRIL C9 (RENIN-ANGIOTEN SYS AGENT) C9A0 (ACE INHIBITORS PLAIN) 0 31 Antihypertensives ENALAPRIL C9 (RENIN-ANGIOTEN SYS AGENT) C9A0 (ACE INHIBITORS PLAIN) 1 Antihypertensives EPROSARTAN C9 (RENIN-ANGIOTEN SYS AGENT) C9C0 (ANGIOTEN-II ANTAG, PLAIN) 0 32 Antihypertensives FOSINOPRIL C9 (RENIN-ANGIOTEN SYS AGENT) C9A0 (ACE INHIBITORS PLAIN) 0 33 Antihypertensives FOSINOPRIL#HYDROCHLOROTHIAZIDE C9 (RENIN-ANGIOTEN SYS AGENT) C9B1 (ACE INH COMB+A-HYP/DIUR) 0 Antihypertensives HYDROCHLOROTHIAZIDE#IRBESARTAN C9 (RENIN-ANGIOTEN SYS AGENT) C9D1 (AT2 ANTG COMB C2 &/O DIU) 0 34 Antihypertensives HYDROCHLOROTHIAZIDE#LOSARTAN C9 (RENIN-ANGIOTEN SYS AGENT) C9D1 (AT2 ANTG COMB C2 &/O DIU) 0 35 Antihypertensives HYDROCHLOROTHIAZIDE#OLMESARTAN MEDOXOMIL C9 (RENIN-ANGIOTEN SYS AGENT) C9D1 (AT2 ANTG COMB C2 &/O DIU) 0 Antihypertensives HYDROCHLOROTHIAZIDE#QUINAPRIL C9 (RENIN-ANGIOTEN SYS AGENT) C9B1 (ACE INH COMB+A-HYP/DIUR) 0 36 Antihypertensives HYDROCHLOROTHIAZIDE#RAMIPRIL C9 (RENIN-ANGIOTEN SYS AGENT) C9B1 (ACE INH COMB+A-HYP/DIUR) 0 37 Antihypertensives HYDROCHLOROTHIAZIDE#TELMISARTAN C9 (RENIN-ANGIOTEN SYS AGENT) C9D1 (AT2 ANTG COMB C2 &/O DIU) 0 Antihypertensives HYDROCHLOROTHIAZIDE#VALSARTAN C9 (RENIN-ANGIOTEN SYS AGENT) C9D1 (AT2 ANTG COMB C2 &/O DIU) 0 38 Antihypertensives IMIDAPRIL C9 (RENIN-ANGIOTEN SYS AGENT) C9A0 (ACE INHIBITORS PLAIN) 0 39 Antihypertensives INDAPAMIDE#PERINDOPRIL C9 (RENIN-ANGIOTEN SYS AGENT) C9B1 (ACE INH COMB+A-HYP/DIUR) 0 Antihypertensives IRBESARTAN C9 (RENIN-ANGIOTEN SYS AGENT) C9C0 (ANGIOTEN-II ANTAG, PLAIN) 0 40 Antihypertensives LISINOPRIL C9 (RENIN-ANGIOTEN SYS AGENT) C9A0 (ACE INHIBITORS PLAIN ) 0 41 Antihypertensives LOSARTAN C9 (RENIN-ANGIOTEN SYS AGENT) C9C0 (ANGIOTEN-II ANTAG, PLAIN) 0 Antihypertensives OLMESARTAN MEDOXOMIL C9 (RENIN-ANGIOTEN SYS AGENT) C9C0 (ANGIOTEN-II ANTAG, PLAIN) 0 42 Antihypertensives PERINDOPRIL C9 (RENIN-ANGIOTEN SYS AGENT) C9A0 (ACE INHIBITORS PLAIN ) 0 43 Antihypertensives QUINAPRIL C9 (RENIN-ANGIOTEN SYS AGENT) C9A0 (ACE INHIBITORS PLAIN ) 0 Antihypertensives RAMIPRIL C9 (RENIN-ANGIOTEN SYS AGENT) C9A0 (ACE INHIBITORS PLAIN) 0 44 Antihypertensives TELMISARTAN C9 (RENIN-ANGIOTEN SYS AGENT) C9C0 (ANGIOTEN-II ANTAG, PLAIN) 0 45 Antihypertensives VALSARTAN C9 (RENIN-ANGIOTEN SYS AGENT) C9C0 (ANGIOTEN-II ANTAG, PLAIN) 0 Cardiac Therapy ADENOSINE C1 (CARDIAC THERAPY) C1B0 (ANTIARRHYTHMICS) 0 46 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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Cardiac Therapy AMIODARONE C1 (CARDIAC THERAPY) C1B0 (ANTIARRHYTHMICS) 1 1 Cardiac Therapy AMRINONE C1 (CARDIAC THERAPY) C1F0 (POSITIVE INOTROPIC AGENT) 0 Cardiac Therapy CAFFEINE#ETAMIVAN C1 (CARDIAC THERAPY) C1C1 (CARDIAC STM EX DOPAM AGT) 0 2 Cardiac Therapy DIGITALIS PURPUREA C1 (CARDIAC THERAPY) C1A1 (CARDIAC GLYCOSIDES PLAIN) 0 3 Cardiac Therapy DIGITOXIN C1 (CARDIAC THERAPY) C1A1 (CARDIAC GLYCOSIDES PLAIN) 0 Cardiac Therapy DIGOXIN C1 (CARDIAC THERAPY) C1A1 (CARDIAC GLYCOSIDES PLAIN) 1 4 Cardiac Therapy DISOPYRAMIDE C1 (CARDIAC THERAPY) C1B0 (ANTIARRHYTHMICS) 0 5 Cardiac Therapy DOBUTAMINE C1 (CARDIAC THERAPY) C1C2 (CARDIAC DOPAMINERG AGENT) 1 Cardiac Therapy DOPAMINE C1 (CARDIAC THERAPY) C1C2 (CARDIAC DOPAMINERG AGENT) 1 6 Cardiac Therapy EPINEPHRINE C1 (CARDIAC THERAPY) C1C1 (CARDIAC STM EX DOPAM AGT) 1 7 Cardiac Therapy ETAFEDRINE C1 (CARDIAC THERAPY) C1C1 (CARDIAC STM EX DOPAM AGT) 0 Cardiac Therapy ETILEFRINE C1 (CARDIAC THERAPY) C1C1 (CARDIAC STM EX DOPAM AGT) 0 8 Cardiac Therapy FLECAINIDE C1 (CARDIAC THERAPY) C1B0 (ANTIARRHYTHMICS) 0 9 Cardiac Therapy GLYCINE MAX#UBIDECARENONE C1 (CARDIAC THERAPY) C1X0 (ALL OTHER CARDIAC PREPS) 0 Cardiac Therapy ISOPRENALINE C1 (CARDIAC THERAPY) C1C1 (CARDIAC STM EX DOPAM AGT) 0 10 Cardiac Therapy ISOSORBIDE DINITRATE C1 (CARDIAC THERAPY) C1E0 (NITRITES AND NITRATES) 1 11 Cardiac Therapy ISOSORBIDE MONONITRATE C1 (CARDIAC THERAPY) C1E0 (NITRITES AND NITRATES) 1 Cardiac Therapy IVABRADINEFor peer C1 review(CARDIAC THERAPY) C1D0 (CORONRY only THER EXC C AN+NI) 0 12 Cardiac Therapy LIDOCAINE C1 (CARDIAC THERAPY) C1B0 (ANTIARRHYTHMICS) 1 13 Cardiac Therapy MAGNESIUM#POTASSIUM#PROCAINE C1 (CARDIAC THERAPY) C1X0 (ALL OTHER CARDIAC PREPS) 0 Cardiac Therapy METARAMINOL C1 (CARDIAC THERAPY) C1C1 (CARDIAC STM EX DOPAM AGT) 1 14 Cardiac Therapy METILDIGOXIN C1 (CARDIAC THERAPY) C1A1 (CARDIAC GLYCOSIDES PLAIN) 0 15 Cardiac Therapy MEXILETINE C1 (CARDIAC THERAPY) C1B0 (ANTIARRHYTHMICS) 0 Cardiac Therapy MIDODRINE C1 (CARDIAC THERAPY) C1C1 (CARDIAC STM EX DOPAM AGT) 0 16 Cardiac Therapy MILRINONE C1 (CARDIAC THERAPY) C1F0 (POSITIVE INOTROPIC AGENT) 0 17 Cardiac Therapy NITROGLYCERIN C1 (CARDIAC THERAPY) C1E0 (NITRITES AND NITRATES) 0 Cardiac Therapy NOREPINEPHRINE C1 (CARDIAC THERAPY) C1C1 (CARDIAC STM EX DOPAM AGT) 0 only listed in combo with lidocaide 18 Cardiac Therapy OXYFEDRINE C1 (CARDIAC THERAPY) C1D0 (CORONRY THER EXC C AN+NI) 0 19 Cardiac Therapy PENTAERYTHRITYL TETRANITRATE C1 (CARDIAC THERAPY) C1E0 (NITRITES AND NITRATES) http://bmjopen.bmj.com/ 0 Cardiac Therapy PROCAINAMIDE C1 (CARDIAC THERAPY) C1B0 (ANTIARRHYTHMICS) 1 20 Cardiac Therapy PROPAFENONE C1 (CARDIAC THERAPY) C1B0 (ANTIARRHYTHMICS) 1 21 Cardiac Therapy QUINIDINE C1 (CARDIAC THERAPY) C1B0 (ANTIARRHYTHMICS) 0 Cardiac Therapy TOCAINIDE C1 (CARDIAC THERAPY) C1B0 (ANTIARRHYTHMICS) 0 22 Cardiac Therapy TRIMETAZIDINE C1 (CARDIAC THERAPY) C1D0 (CORONRY THER EXC C AN+NI) 0 23 Cardiac Therapy UBIDECARENONE C1 (CARDIAC THERAPY) C1X0 (ALL OTHER CARDIAC PREPS) 0 Cardiac Therapy UBIQUINONE(S) C1 (CARDIAC THERAPY) C1X0 (ALL OTHER CARDIAC PREPS) 0 24 Lipid Regulating ACIPIMOX C10 (LIP.REG./ANTI-ATH. PREPS) C10A9 (OTH.CHOLEST&TRIGLY.REGUL) 0 25 Lipid Regulating ALLIUM SATIVUM C10 (LIP.REG./ANTI-ATH. PREPS) C10B0 (ANTI-ATHEROMA NATRL ORIG) 0 Lipid Regulating ALLIUM SATIVUM#ARACHIS HYPOGAEA C10 (LIP.REG./ANTI-ATH. PREPS) C10B0 (ANTI-ATHEROMA NATRL ORIG) 0 26 Lipid Regulating ALLIUM SATIVUM#SOYA LECITHIN C10 (LIP.REG./ANTI-ATH. PREPS) C10B0 (ANTI-ATHEROMA NATRL ORIG) 0

27 Lipid Regulating AMLODIPINE#ATORVASTATIN C11 (C.V. MULTITH. COMB PROD) C11A1 (LIPREG.CV.MULT-TH.FX.COM) on September 26, 2021 by guest. Protected copyright. 0 Lipid Regulating ATORVASTATIN C10 (LIP.REG./ANTI-ATH. PREPS) C10A1 (STATINS (HMG-COA RED)) 0 28 Lipid Regulating BEZAFIBRATE C10 (LIP.REG./ANTI-ATH. PREPS) C10A2 (FIBRATES) 0 29 Lipid Regulating CERIVASTATIN C10 (LIP.REG./ANTI-ATH. PREPS) C10A1 (STATINS (HMG-COA RED)) 0 Lipid Regulating COLESTYRAMINE C10 (LIP.REG./ANTI-ATH. PREPS) C10A3 (ION-EXCHANGE RESINS) 0 30 Lipid Regulating DOCOSAHEXANOIC ACID#EICOSAPENTAENOIC ACID C10 (LIP.REG./ANTI-ATH. PREPS) C10B0 (ANTI-ATHEROMA NATRL ORIG) 0 31 Lipid Regulating DOCOSAHEXANOIC ACID#EICOSAPENTAENOIC ACID#VITAMIN E C10 (LIP.REG./ANTI-ATH. PREPS) C10B0 (ANTI-ATHEROMA NATRL ORIG) 0 Lipid Regulating EZETIMIBE C10 (LIP.REG./ANTI-ATH. PREPS) C10A9 (OTH.CHOLEST&TRIGLY.REGUL) 0 32 Lipid Regulating EZETIMIBE#SIMVASTATIN C10 (LIP.REG./ANTI-ATH. PREPS) C10C0 (LIP.REG.CO.W.OTH.LIP.REG) 0 33 Lipid Regulating FENOFIBRATE C10 (LIP.REG./ANTI-ATH. PREPS) C10A2 (FIBRATES) 0 Lipid Regulating FISH C10 (LIP.REG./ANTI-ATH. PREPS) C10B0 (ANTI-ATHEROMA NATRL ORIG) 0 34 Lipid Regulating FISH#SOYA LECITHIN C10 (LIP.REG./ANTI-ATH. PREPS) C10B0 (ANTI-ATHEROMA NATRL ORIG) 0 35 Lipid Regulating FLUVASTATIN C10 (LIP.REG./ANTI-ATH. PREPS) C10A1 (STATINS (HMG-COA RED) ) 0 Lipid Regulating GEMFIBROZIL C10 (LIP.REG./ANTI-ATH. PREPS) C10A2 (FIBRATES) 1 36 Lipid Regulating LECITHIN C10 (LIP.REG./ANTI-ATH. PREPS) C10B0 (ANTI-ATHEROMA NATRL ORIG) 0 37 Lipid Regulating LECITHIN#SOYA LECITHIN C10 (LIP.REG./ANTI-ATH. PREPS) C10B0 (ANTI-ATHEROMA NATRL ORIG) 0 Lipid Regulating NICOTINIC ACID C10 (LIP.REG./ANTI-ATH. PREPS) C10A9 (OTH.CHOLEST&TRIGLY.REGUL) 1 38 Lipid Regulating PITAVASTATIN C10 (LIP.REG./ANTI-ATH. PREPS) C10A1 (STATINS (HMG-COA RED)) 0 39 Lipid Regulating PRAVASTATIN C10 (LIP.REG./ANTI-ATH. PREPS) C10A1 (STATINS (HMG-COA RED)) 1 Lipid Regulating PROBUCOL C10 (LIP.REG./ANTI-ATH. PREPS) C10A9 (OTH.CHOLEST&TRIGLY.REGUL) 0 40 Lipid Regulating PYRICARBATE C10 (LIP.REG./ANTI-ATH. PREPS) C10A9 (OTH.CHOLEST&TRIGLY.REGUL) 0 41 Lipid Regulating ROSUVASTATIN C10 (LIP.REG./ANTI-ATH. PREPS) C10A1 (STATINS (HMG-COA RED)) 0 Lipid Regulating SALMON C10 (LIP.REG./ANTI-ATH. PREPS) C10B0 (ANTI-ATHEROMA NATRL ORIG) 1 listed as "calcitonic salmon" on NLEM 42 Lipid Regulating SIMVASTATIN C10 (LIP.REG./ANTI-ATH. PREPS) C10A1 (STATINS (HMG-COA RED)) 1 43 Lipid Regulating SOYA LECITHIN C10 (LIP.REG./ANTI-ATH. PREPS) C10B0 (ANTI-ATHEROMA NATRL ORIG) 0

44 CANCER 45 Antineoplastics ALEMTUZUMAB L1 (ANTINEOPLASTICS) L1X3 (ANTINEOPLASTIC MABS) 0 Antineoplastics ALTRETAMINE L1 (ANTINEOPLASTICS) L1A0 (ALKYLATING AGENTS) 0 46 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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Antineoplastics ASPARAGINASE L1 (ANTINEOPLASTICS) L1X9 (ALL OTH. ANTINEOPLASTICS) 0 1 Antineoplastics AZACITIDINE L1 (ANTINEOPLASTICS) L1B0 (ANTIMETABOLITES) 0 Antineoplastics BEVACIZUMAB L1 (ANTINEOPLASTICS) L1X3 (ANTINEOPLASTIC MABS) 0 2 Antineoplastics BLEOMYCIN L1 (ANTINEOPLASTICS) L1D0 (ANTINEOPLAS. ANTIBIOTICS) 1 3 Antineoplastics BORTEZOMIB L1 (ANTINEOPLASTICS) L1X9 (ALL OTH. ANTINEOPLASTICS) 0 Antineoplastics BUSULFAN L1 (ANTINEOPLASTICS) L1A0 (ALKYLATING AGENTS) 1 4 Antineoplastics CAPECITABINE L1 (ANTINEOPLASTICS) L1B0 (ANTIMETABOLITES) 0 5 Antineoplastics CARBOPLATIN L1 (ANTINEOPLASTICS) L1X2 (PLATINUM COMPOUNDS) 1 Antineoplastics CARMUSTINE L1 (ANTINEOPLASTICS) L1A0 (ALKYLATING AGENTS) 1 6 Antineoplastics CETUXIMAB L1 (ANTINEOPLASTICS) L1X3 (ANTINEOPLASTIC MABS) 0 7 Antineoplastics CHLORAMBUCIL L1 (ANTINEOPLASTICS) L1A0 (ALKYLATING AGENTS) 1 Antineoplastics CHLORMETHINE L1 (ANTINEOPLASTICS) L1A0 (ALKYLATING AGENTS ) 0 8 Antineoplastics CISPLATIN L1 (ANTINEOPLASTICS) L1X2 (PLATINUM COMPOUNDS) 1 9 Antineoplastics CLADRIBINE L1 (ANTINEOPLASTICS) L1B0 (ANTIMETABOLITES) 0 Antineoplastics CYCLOPHOSPHAMIDE L1 (ANTINEOPLASTICS) L1A0 (ALKYLATING AGENTS) 1 10 Antineoplastics CYTARABINE L1 (ANTINEOPLASTICS) L1B0 (ANTIMETABOLITES) 1 11 Antineoplastics DACARBAZINE L1 (ANTINEOPLASTICS) L1A0 (ALKYLATING AGENTS) 0 Antineoplastics DACTINOMYCINFor peer L1 (ANTINEOPLASTICS)review L1D0 (ANTINEOPLAS. only ANTIBIOTICS) 1 12 Antineoplastics DASATINIB L1 (ANTINEOPLASTICS) L1X4 (A-NEO PROTEIN KINASE INH) 0 13 Antineoplastics DECITABINE L1 (ANTINEOPLASTICS) L1B0 (ANTIMETABOLITES) 0 Antineoplastics DOCETAXEL L1 (ANTINEOPLASTICS) L1C0 (VINCA ALKALOIDS ) 0 14 Antineoplastics DOXORUBICIN L1 (ANTINEOPLASTICS) L1D0 (ANTINEOPLAS. ANTIBIOTICS) 1 15 Antineoplastics EPIRUBICIN L1 (ANTINEOPLASTICS) L1D0 (ANTINEOPLAS. ANTIBIOTICS) 1 Antineoplastics ERLOTINIB L1 (ANTINEOPLASTICS) L1X4 (A-NEO PROTEIN KINASE INH) 0 16 Antineoplastics ETOPOSIDE L1 (ANTINEOPLASTICS) L1C0 (VINCA ALKALOIDS) 1 17 Antineoplastics FLUDARABINE L1 (ANTINEOPLASTICS) L1B0 (ANTIMETABOLITES) 0 Antineoplastics FLUOROURACIL L1 (ANTINEOPLASTICS) L1B0 (ANTIMETABOLITES) 1 18 Antineoplastics GEFITINIB L1 (ANTINEOPLASTICS) L1X4 (A-NEO PROTEIN KINASE INH) 0 19 Antineoplastics GEMCITABINE L1 (ANTINEOPLASTICS) L1B0 (ANTIMETABOLITES) http://bmjopen.bmj.com/ 0 Antineoplastics HYDROXYCARBAMIDE L1 (ANTINEOPLASTICS) L1X9 (ALL OTH. ANTINEOPLASTICS) 0 20 Antineoplastics IBRITUMOMAB TIUXETAN L1 (ANTINEOPLASTICS) L1X3 (ANTINEOPLASTIC MABS) 0 21 Antineoplastics IDARUBICIN L1 (ANTINEOPLASTICS) L1D0 (ANTINEOPLAS. ANTIBIOTICS) 1 Antineoplastics IFOSFAMIDE L1 (ANTINEOPLASTICS) L1A0 (ALKYLATING AGENTS) 1 22 Antineoplastics IMATINIB L1 (ANTINEOPLASTICS) L1X4 (A-NEO PROTEIN KINASE INH) 0 23 Antineoplastics IRINOTECAN L1 (ANTINEOPLASTICS) L1C0 (VINCA ALKALOIDS) 0 Antineoplastics IXABEPILONE L1 (ANTINEOPLASTICS) L1X9 (ALL OTH. ANTINEOPLASTICS) 0 24 Antineoplastics LAPATINIB L1 (ANTINEOPLASTICS) L1X4 (A-NEO PROTEIN KINASE INH) 0 25 Antineoplastics LOMUSTINE L1 (ANTINEOPLASTICS) L1A0 (ALKYLATING AGENTS) 1 Antineoplastics MELPHALAN L1 (ANTINEOPLASTICS) L1A0 (ALKYLATING AGENTS) 1 26 Antineoplastics MERCAPTOPURINE L1 (ANTINEOPLASTICS) L1B0 (ANTIMETABOLITES) 1

27 Antineoplastics METHOTREXATE L1 (ANTINEOPLASTICS) L1B0 (ANTIMETABOLITES) on September 26, 2021 by guest. Protected copyright. 1 Antineoplastics MITOMYCIN L1 (ANTINEOPLASTICS) L1D0 (ANTINEOPLAS. ANTIBIOTICS) 1 28 Antineoplastics MITOXANTRONE L1 (ANTINEOPLASTICS) L1D0 (ANTINEOPLAS. ANTIBIOTICS) 0 29 Antineoplastics NILOTINIB L1 (ANTINEOPLASTICS) L1X4 (A-NEO PROTEIN KINASE INH) 0 Antineoplastics OXALIPLATIN L1 (ANTINEOPLASTICS) L1X2 (PLATINUM COMPOUNDS) 0 30 Antineoplastics PACLITAXEL L1 (ANTINEOPLASTICS) L1C0 (VINCA ALKALOIDS) 1 31 Antineoplastics PEMETREXED L1 (ANTINEOPLASTICS) L1B0 (ANTIMETABOLITES) 0 Antineoplastics PROCARBAZINE L1 (ANTINEOPLASTICS) L1X9 (ALL OTH. ANTINEOPLASTICS) 1 32 Antineoplastics RITUXIMAB L1 (ANTINEOPLASTICS) L1X3 (ANTINEOPLASTIC MABS) 0 33 Antineoplastics SORAFENIB L1 (ANTINEOPLASTICS) L1X4 (A-NEO PROTEIN KINASE INH) 0 Antineoplastics SUNITINIB L1 (ANTINEOPLASTICS) L1X4 (A-NEO PROTEIN KINASE INH) 0 34 Antineoplastics TEGAFUR L1 (ANTINEOPLASTICS) L1B0 (ANTIMETABOLITES) 0 35 Antineoplastics TEGAFUR#URACIL L1 (ANTINEOPLASTICS) L1B0 (ANTIMETABOLITES) 1 Antineoplastics TEMOZOLOMIDE L1 (ANTINEOPLASTICS) L1A0 (ALKYLATING AGENTS) 0 36 Antineoplastics TIOGUANINE L1 (ANTINEOPLASTICS) L1B0 (ANTIMETABOLITES) 0 37 Antineoplastics TOPOTECAN L1 (ANTINEOPLASTICS) L1C0 (VINCA ALKALOIDS) 0 Antineoplastics TRASTUZUMAB L1 (ANTINEOPLASTICS) L1X3 (ANTINEOPLASTIC MABS) 0 38 Antineoplastics TRETINOIN L1 (ANTINEOPLASTICS) L1X9 (ALL OTH. ANTINEOPLASTICS) 0 39 Antineoplastics VINBLASTINE L1 (ANTINEOPLASTICS) L1C0 (VINCA ALKALOIDS) 1 Antineoplastics VINCRISTINE L1 (ANTINEOPLASTICS) L1C0 (VINCA ALKALOIDS) 1 40 Antineoplastics VINORELBINE L1 (ANTINEOPLASTICS) L1C0 (VINCA ALKALOIDS) 0 41 Cytostatic Hormones AMINOGLUTETHIMIDE L2 (CYTOSTATIC HORMONE THER) L2B3 (CYTOSTAT AROMATASE INHIB) 0 Cytostatic Hormones ANASTROZOLE L2 (CYTOSTATIC HORMONE THER) L2B3 (CYTOSTAT AROMATASE INHIB) 0 42 Cytostatic Hormones BICALUTAMIDE L2 (CYTOSTATIC HORMONE THER) L2B2 (CYTO ANTI-ANDROGENS) 0 43 Cytostatic Hormones BUSERELIN L2 (CYTOSTATIC HORMONE THER) L2A3 (CYTO GONAD HORMON ANALOG) 1 Cytostatic Hormones CYPROTERONE L2 (CYTOSTATIC HORMONE THER) L2B2 (CYTO ANTI-ANDROGENS) 1 44 Cytostatic Hormones EXEMESTANE L2 (CYTOSTATIC HORMONE THER) L2B3 (CYTOSTAT AROMATASE INHIB) 0 45 Cytostatic Hormones FLUTAMIDE L2 (CYTOSTATIC HORMONE THER) L2B2 (CYTO ANTI-ANDROGENS) 1 Cytostatic Hormones FORMESTANE L2 (CYTOSTATIC HORMONE THER) L2B3 (CYTOSTAT AROMATASE INHIB) 1 46 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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Cytostatic Hormones FULVESTRANT L2 (CYTOSTATIC HORMONE THER) L2B9 (OTH CYTO HORMON ANTAGIST) 0 1 Cytostatic Hormones GOSERELIN L2 (CYTOSTATIC HORMONE THER) L2A3 (CYTO GONAD HORMON ANALOG) 1 Cytostatic Hormones LETROZOLE L2 (CYTOSTATIC HORMONE THER) L2B3 (CYTOSTAT AROMATASE INHIB) 0 2 Cytostatic Hormones LEUPRORELIN L2 (CYTOSTATIC HORMONE THER) L2A3 (CYTO GONAD HORMON ANALOG) 1 3 Cytostatic Hormones MEDROXYPROGESTERONE L2 (CYTOSTATIC HORMONE THER) L2A2 (CYTOSTATIC PROGESTOGENS ) 0 Cytostatic Hormones MEGESTROL L2 (CYTOSTATIC HORMONE THER) L2A2 (CYTOSTATIC PROGESTOGENS ) 1 4 Cytostatic Hormones TAMOXIFEN L2 (CYTOSTATIC HORMONE THER) L2B1 (CYTO ANTI-OESTROGENS) 1 5 Cytostatic Hormones TOREMIFENE L2 (CYTOSTATIC HORMONE THER) L2B1 (CYTO ANTI-OESTROGENS) 0 Cytostatic Hormones TRIPTORELIN L2 (CYTOSTATIC HORMONE THER) L2A3 (CYTO GONAD HORMON ANALOG) 0 6 Immunostimulating Agents FILGRASTIM L3 (IMMUNOSTIMULATING AGENTS) L3A1 (COLONY-STIMULATING FACT.) 1 7 Immunostimulating Agents INTERFERON ALFA L3 (IMMUNOSTIMULATING AGENTS) L3B1 (INTERFERONS ALPHA) 0 Immunostimulating Agents INTERFERON ALFA-2A L3 (IMMUNOSTIMULATING AGENTS) L3B1 (INTERFERONS ALPHA) 0 8 Immunostimulating Agents INTERFERON ALFA-2B L3 (IMMUNOSTIMULATING AGENTS) L3B1 (INTERFERONS ALPHA) 0 9 Immunostimulating Agents INTERFERON ALFA-N1 L3 (IMMUNOSTIMULATING AGENTS) L3B1 (INTERFERONS ALPHA) 0 Immunostimulating Agents INTERFERON BETA-1A L3 (IMMUNOSTIMULATING AGENTS) L3B2 (INTERFERONS BETA) 0 10 Immunostimulating Agents INTERFERON BETA-1B L3 (IMMUNOSTIMULATING AGENTS) L3B2 (INTERFERONS BETA) 0 11 Immunostimulating Agents LENOGRASTIM L3 (IMMUNOSTIMULATING AGENTS) L3A1 (COLONY-STIMULATING FACT.) 1 Immunostimulating Agents MOLGRAMOSTIMFor peer L3 (IMMUNOSTIMULATINGreview AGENTS) L3A1 (COLONY-STIMULATING only FACT.) 1 12 Immunostimulating Agents PEGFILGRASTIM L3 (IMMUNOSTIMULATING AGENTS) L3A1 (COLONY-STIMULATING FACT.) 0 13 Immunostimulating Agents TETRACHLORODECAOXIDE L3 (IMMUNOSTIMULATING AGENTS) L3A9 (OTH.IMMUNOSTIM.EX.INTFRN) 0 Immunostimulating Agents THYMALFASIN L3 (IMMUNOSTIMULATING AGENTS) L3A9 (OTH.IMMUNOSTIM.EX.INTFRN) 0 14 15 16 17 18 19 http://bmjopen.bmj.com/ 20 21 22 23 24 25 26

27 on September 26, 2021 by guest. Protected copyright. 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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1 2 Appendix Table 2. Segmented Regression Coefficients: Total Volume* 3 4 INTERCEPT TIME INTERVENTION TIME AFTER INTERVENTION TIME AFTER INTERVENTION SQUARED** 5 Beta Beta (Std. Err.) Beta (Std. Err.) Beta (Std. Err.) Beta (Std. Err.) 6 DIABETES 7 Insulins 8 Hospital 1.6941 0.0848 (0.0185) 0.5151 (0.2400) 0.0961 (0.0432) 0.0156 (0.0019) 9 Retail 0.3485 -0.0134 (0.0041) 0.0902 (0.0445) 0.0288 (0.0046) - 10 11 Antidiabetics For peer review only 12 Hospital 1252.37 71.08 (12.05) 66.40 (167.31) 12.80 (26.17) 3.08 (1.24) 13 Retail 228.87 6.67 (3.01) -63.98 (32.56) -1.88 (3.37) - 14 15 CARDIOVASCULAR DISEASE 16 Antihypertensives 17 Hospital 1394.24 111.96 (17.14) -390.49 (185.18) 71.95 (19.17) - 18 Retail 284.98 8.12 (2.24) -39.71 (24.19) 5.20 (2.50) - 19 http://bmjopen.bmj.com/ 20 Lipid Regulating Agents 21 Hospital 193.47 17.31 (3.33) -37.98 (43.19) -6.02 (7.78) 2.77 (0.34) 22 Retail 136.25 -2.59 (1.31) -21.37 (14.18) 11.72 (1.47) - 23 24 Cardiac Therapy 25 Hospital 434.75 13.92 (4.11) -94.51 (44.37) 0.63 (4.59) - 26 Retail 98.32 1.63 (1.18) 11.50 (15.31) -8.80 (2.76) 0.32 (0.12)

27 on September 26, 2021 by guest. Protected copyright. 28 CANCER 29 Antineoplastics 30 Hospital 21.75 0.72 (0.16) -2.02 (1.78) 0.21 (0.18) - 31 Retail 0.26 0.004 (0.02) 0.18 (0.37) 0.05 (0.06) -0.005 (0.002) 32 33 Cytostatic Hormones 34 Hospital 16.38 0.69 (0.15) -0.66 (1.60) 0.44 (0.17) - 35 Retail 0.3538 -0.03 (0.01) 0.53 (0.13) -0.03 (0.02) 0.004 (0.001) 36 37 Immunostimulating Agents 38 Hospital 0.45 0.01 (0.004) -0.18 (0.05) -0.02 (0.008) 0.0007 (0.0004) 39 Retail 0.0000066 -0.0000005 (0.000001) 0.0000003 (0.000007) 0.0000005 (0.0000007) - 40 41 * Bold signifies statistically significant coefficient (i.e., p<0.05) 42 **Results from quadratic model (which has squared post-policy trend term) were included if quadratic model fits better than linear model. 43 44 45 46 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 30 of 52 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 Appendix Table 3. Summary of Hospital Sector Volume Regression Results by NLEM* 4 5 6 Therapeutic Area Pre-policy trend Immediate change after policy Post-policy trend change 7 8 DIABETES 9 Antidiabetics 10 11 NLEM** h h 12 non-NLEM** h h 13 Insulins *** 14 15 NLEM** For peerh reviewh only h 16 non-NLEM 17 18 19 CARDIOVASCULAR DISEASE 20 Antihypertensives 21 NLEM h h 22 23 non-NLEM** h h 24 Lipid Regulating Agents 25 NLEM** 26 h h 27 non-NLEM** h i h 28 Cardiac Therapy 29 30 NLEM h 31 non-NLEM** h i 32 33 CANCER

34 http://bmjopen.bmj.com/ 35 Antineoplastics 36 NLEM h 37 38 non-NLEM** h 39 Cytostatic Hormones 40 NLEM h 41 42 non-NLEM** h h h on September 26, 2021 by guest. Protected copyright. 43 Immunostimulating Agents 44 NLEM** h 45 46 non-NLEM i i 47 48 *Arrows signify a statistically significant coefficient (p<0.05) from segmented regression. Volume is population adjusted - denominator is 49 entire population for insulins and over-15 population for rest of therapeutic areas. 50 **Quadratic model (which has a squared time-after term) fits beter than linear model. 51 Details: - Both after and after-squared terms were significant for insulins, non-NLEM antidiabetics, non- 52 NLEM antihypertensives 53 - Only after-squared term was significant for NLEM antidiabetics and NLEM lipid regulators 54 - Only linear after term was significant for non-NLEM immunostimulating agents 55 - The linear after term for nonNLEM antidiabetics and nonNLEM lipid reg was negative, but the 56 positive after-squared term meant a long-term increase in trend 57 ***All insulins are classified as NLEM medicines 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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1 2 3 4 Appendix Table 4. Absolute Impact of the Reform on Sales of Medicines by Class (one and five years post-policy)* 5 6 Therapeutic Class One Year Impact (in standard units) Five Year Impact (in standard units) 7 Predicted Observed Absolute Change (95% CI) Predicted Observed Absolute Change (95% CI) 8 Antidiabetics 2602.91 2769.79 166.87 (-160.98, 494.73) 3669.13 5090.62 1421.49 (739.57, 2103.42) 9 10 Insulins 3.30 4.45 1.15 (0.66, 1.64) 4.58 12.56 7.98 (6.94, 9.02) 11 Cardiac Therapy Agents For699.28 peer607.27 -92.01review (-201.38, 17.36) 908.12only825.49 -82.63 (-309.66, 144.40) 12 Lipid Regulating Agents 522.34 504.58 -17.76 (-106.50, 70.97) 781.97 1629.11 847.14 (659.98, 1034.30) 13 14 Antihypertensives 3521.47 3418.79 -102.68 (-559.16, 353.80) 5200.86 6177.49 976.62 (29.03, 1924.22) 15 Antineoplastics 35.38 34.21 -1.17 (-5.56, 3.22) 46.14 48.13 1.99 (-7.13, 11.11) 16 Cytostatic Hormones 29.48 30.58 1.10 (-2.85, 5.05) 39.82 47.52 7.70 (-0.50, 15.89) 17 Immunostimulating Agents 0.65 0.43 -0.23 (-0.32, -0.13) 0.81 0.60 -0.21 (-0.42, -0.01) 18 19 http://bmjopen.bmj.com/ *bold signifies that change is statistically significant (i.e., confidence interval does not include the null value of 0) 20 21 22 23 24 25 26

27 on September 26, 2021 by guest. Protected copyright. 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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Appendix Table 5. Segmented Regression Coefficients: Hospital Market Share* 1 2 INTERCEPT TIME INTERVENTION TIME AFTER INTERVENTION TIME AFTER INTERVENTION SQUARED** 3 Beta Beta (Std. Err.) Beta (Std. Err.) Beta (Std. Err.) Beta (Std. Err.) 4 Insulins (Hospital) 5 Originator Brand -0.0017 0.0005 (0.0001) -0.0004 (0.0017) -0.0003 (0.0003) 0.0001 (0.0000002) 6 Branded Generic 0.8934 0.0026 (0.0019) 0.0697 (0.0200) -0.0048 (0.0021) - 7 Generic 0.1083 -0.0030 (0.0019) -0.0624 (0.0200) 0.0031 (0.0021) - 8 Antidiabetics (Hospital) 9 Originator Brand 0.1601 -0.0049 (0.0006) -0.0028 (0.0064) 0.0042 (0.0007) - 10 Branded Generic 0.5178 0.0010 (0.0016) -0.1233 (0.0178) -0.0045 (0.0017) - 11 Generic For0.0692 peer0.0005 (0.0011) review-0.0345 (0.0116) -0.000545 only (0.0012) - 12 GPO 0.2505 0.0034 (0.0018) 0.1610 (0.0200) 0.000992 (0.0019) - 13 14 Antihypertentives (Hospital) 15 Originator Brand 0.296 -0.0066 (0.0008) -0.0014 (0.0105) 0.0034 (0.0019) 0.0002 (0.00008) 16 Branded Generic 0.4491 0.0056 (0.0015) -0.0214 (0.0191) 0.0092 (0.0034) -0.0006 (0.0002) 17 Generic 0.041 0.0033 (0.0012) -0.0567 (0.0130) -0.0030 (0.0013) - GPO 0.211 -0.0020 (0.0024) 0.0525 (0.0259) -0.0022 (0.0027) - 18 http://bmjopen.bmj.com/ 19 Lipid Regulating Agents (Hospital) 20 Originator Brand 0.5657 -0.0092 (0.0008) -0.0776 (0.0116) -0.0061 (0.0116) 0.0003 (0.00009) 21 Branded Generic 0.427 0.0096 (0.0008) 0.0755 (0.0118) 0.0055 (0.0017) -0.0003 (0.00009) 22 Generic 0.004897 -0.0003 (0.0002) 0.0015 (0.0025) 0.0002 (0.0003) - 23 GPO -0.000482 0.0001 (0.0003) 0.0023 (0.0028) -0.0003 (0.0003) - 24 25 Cardiac Therapy (Hospital) 26 Originator Brand 0.0847 -0.0014 (0.0004) 0.0013 (0.0044) 0.0014 (0.0004) Branded Generic 0.8032 -0.0023 (0.0026) -0.1351 (0.0340) -0.0093 (0.0061) 0.0006 (0.0003) 27 on September 26, 2021 by guest. Protected copyright. Generic 0.005095 0.0031 (0.0009) -0.0426 (0.0093) -0.0030 (0.0010) - 28 GPO 0.0751 0.0015 (0.0030) 0.2155 (0.0319) -0.0010 (0.0033) - 29 30 Antineoplastics (Hospital) 31 Originator Brand 0.1554 0.0015 (0.0009) 0.0110 (0.0103) -0.0014 (0.0010) - 32 Branded Generic 0.5518 -0.0011 (0.0020) -0.0100 (0.0216) 0.0011 (0.0022) - 33 Generic 0.2862 -0.0004 (0.0014) 0.0037 (0.0149) 0.0002 (0.0015) - 34 35 Cytostatic Hormones (Hospital) 36 Originator Brand 0.4664 -0.0032 (0.0022) 0.0038 (0.0280) -0.0127 (0.0050) 0.0007 (0.0002) Branded Generic 0.5141 0.0036 (0.0015) -0.0773 (0.0206) 0.0195 (0.0035) -0.0013 (0.0002) 37 Generic 0.0144 0.0004 (0.0017) 0.0600 (0.0224) -0.0060 (0.0040) 0.0005 (0.0002) 38 39 Immunostimulating Agents (Hospital) 40 Originator Brand 0.9742 0.0007 (0.0015) -0.0636 (0.0162) -0.0113 (0.0017) - 41 Branded Generic -0.000536 0.0001 (0.0013) 0.0450 (0.0137) 0.0108 (0.0014) - 42 Generic -0.000986 0.0002 (0.0001) -0.0016 (0.0009) -0.0003 (0.00009) - 43 44 * Bold signifies statistically significant coefficient (i.e., p<0.05) 45 **Results from quadratic model (which has squared post-policy trend term) were included if quadratic model fits better than linear model. 46 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 33 of 52 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 Appendix Table 6. Absolute Impact of the Reform on Sales of Licensing Status Market Share by Class (one and five years post-policy)* 4 5 Therapeutic Class One Year Impact (in % market share) Five Year Impact (in % market share) 6 Predicted Observed Relative Change (95% CI) Predicted Observed Relative Change (95% CI) 7 Antidiabetics 8 Original/Licensed 0.0672 0.0813 0.0140 (-0.0016, 0.0297) -0.0061 0.0712 0.0773 (0.0448, 0.1098) 9 Other 0.5371 0.3960 -0.1412 (-0.1851, -0.0972) 0.5524 0.3443 -0.2080 (-0.2966, -0.1195) 10 Unbranded 0.0788 0.0421 -0.0367 (-0.0652, -0.0082) 0.0864 0.0415 -0.0449 (-0.1041, 0.0144) 11 GPO 0.3142 0.4792 0.1649 (0.1156, 0.2143) 0.3645 0.5444 0.1798 (0.0805, 0.2792)

12 Insulins 13 Originator Brand 0.0079 0.0081 0.0002 (-0.0035, 0.0038) 0.0156 0.0461 0.0305 (0.0228, 0.0382) 14 Branded Generic 0.9419 0.9925 0.0505 (0.0010, 0.1000) 0.9802 0.9590 -0.0212 (-0.1240, 0.0815) 15 Generic For0.0501 0.0000peer-0.0501 (-0.0994, review -0.0008) 0.0042 only0.0000 -0.0042 (-0.1065, 0.0982) 16 17 Antihypertensives 18 Originator Brand 0.1697 0.1850 0.0153 (-0.0063, 0.0368) 0.0700 0.2010 0.1310 (0.0854, 0.1765) 19 Branded Generic 0.5557 0.5619 0.0062 (-0.0330, 0.0454) 0.6398 0.5890 -0.0507 (-0.1333, 0.0319) Generic 0.1029 0.0341 -0.0688 (-0.1009, -0.0368) 0.1519 0.0373 -0.1145 (-0.1811, -0.0480) 20 GPO 0.1725 0.2160 0.0435 (-0.0203, 0.1074) 0.1420 0.1520 0.0100 (-0.1225, 0.1425) 21 22 Cardiac Therapy 23 Originator Brand 0.0588 0.0656 0.0068 (-0.0041, 0.0176) 0.0384 0.0655 0.0271 (0.0049, 0.0493) 24 Branded Generic 0.7594 0.5961 -0.1633 (-0.2332, -0.0935) 0.7594 0.5961 -0.1633 (-0.2332, -0.0935) 25 Generic 0.1116 0.0113 -0.1002 (-0.1477, -0.0528) 0.1116 0.0113 -0.1002 (-0.1477, -0.0528) 26 GPO 0.1034 0.3149 0.2115 (0.1329, 0.2901) 0.1034 0.3149 0.2115 (0.1329, 0.2901) 27 28 Lipid Regulators Originator Brand 0.3905 0.2942 -0.0963 (-0.1187, -0.0739) 0.2522 0.1838 -0.0684 (-0.1158, -0.0210) 29 Branded Generic 0.6086 0.7010 0.0924 (0.0697, 0.1151) 0.7519 0.8159 0.0640 (0.0160, 0.1119) 30 Generic -0.0009 0.0015 0.0024 (-0.0038, 0.0085) -0.0054 0.0004 0.0058 (-0.0070, 0.0186) 31 GPO 0.0022 0.0033 0.0011 (-0.0058, 0.0079) 0.0044 0.0008 -0.0035 (-0.0177, 0.0106) 32 33 Antineoplastics Originator Brand 0.1840 0.1894 0.0054 (-0.0201, 0.0308) 0.2066 0.1908 -0.0158 (-0.0675, 0.0359) 34 http://bmjopen.bmj.com/ 35 Branded Generic 0.5308 0.5252 -0.0056 (-0.0587, 0.0476) 0.5142 0.5252 0.0110 (-0.0993, 0.1214) 36 Generic 0.2783 0.2827 0.0044 (-0.0323, 0.0412) 0.2721 0.2793 0.0072 (-0.0690, 0.0835)

37 Cytostatic Hormones 38 Originator Brand 0.4058 0.3704 -0.0353 (-0.0928, 0.0222) 0.3579 0.3803 0.0224 (-0.0988, 0.1437) 39 Branded Generic 0.5821 0.5626 -0.0195 (-0.0609, 0.0218) 0.6358 0.4764 -0.1595 (-0.2463, -0.0727) 40 Generic 0.0221 0.0653 0.0432 (-0.0029, 0.0893) 0.0282 0.1393 0.1112 (0.0140, 0.2083) 41 42 Immunostimulating Agents on September 26, 2021 by guest. Protected copyright. 43 Originator Brand 0.9875 0.8787 -0.1087 (-0.1488, -0.0687) 0.9979 0.7198 -0.2781 (-0.3612, -0.1951) 44 Branded Generic 0.0018 0.0902 0.0884 (0.0546, 0.1221) 0.0037 0.2546 0.2509 (0.1808, 0.3210) Generic 0.0036 0.0007 -0.0028 (-0.0050, -0.0007) 0.0071 -0.0003 -0.0074 (-0.0120, -0.0029) 45

46 *bold signifies that change is statistically significant (i.e., confidence interval does not include the null value of 0) 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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1 2 3 Appendix Figure 1. Standard Units Per Capita by Quarter 4 5 Insulin (Hospital vs. Retail) 6 7 14 8 9 10 11 12 For peer review only 12 13

14 15 10 16 17 18 19 http://bmjopen.bmj.com/ 20 8 21 22 Hospital Insulin 23 Retail Insulin 24 6 * 25 Hospital Regression Line 26 Retail Regression Line

27 on September 26, 2021 by guest. Protected copyright. Predicted Hospital Regression Line 28 4 29 30 Number Standardof Units per 1000people 31 32 33 2 34 35 36 37 0 38 39

40 1998Q2 1998Q3 1998Q4 1999Q1 1999Q2 1999Q3 1999Q4 2000Q1 2000Q2 2000Q3 2000Q4 2001Q1 2001Q2 2001Q3 2001Q4 2002Q1 2002Q2 2002Q3 2002Q4 2003Q1 2003Q2 2003Q3 2003Q4 2004Q1 2004Q2 2004Q3 2004Q4 2005Q1 2005Q2 2005Q3 2005Q4 2006Q1 2006Q2 2006Q3 41 Quarter 42 43 *Results from quadratic model 44 45 46 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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1 2 3 Appendix Figure 2. Standard Units Per Capita by Quarter 4 5 Antidiabetics (Hospital vs. Retail) 6 6000 7 8 9 10 11 For peer review only 12 5000 13

14 15 16 17 4000 18 19 http://bmjopen.bmj.com/ 20 21 Hospital Antidiabetics 22 3000 23 Retail Antidiabetics 24 25 Hospital Regression Line* 26 Retail Regression Line

27 on September 26, 2021 by guest. Protected copyright. 28 2000 Predicted Hospital Regression Line 29

30 Number Standardof Units per 1000people 31 32 33 1000 34 35 36 37 38 0 39 40

41 1998Q2 1998Q3 1998Q4 1999Q1 1999Q2 1999Q3 1999Q4 2000Q1 2000Q2 2000Q3 2000Q4 2001Q1 2001Q2 2001Q3 2001Q4 2002Q1 2002Q2 2002Q3 2002Q4 2003Q1 2003Q2 2003Q3 2003Q4 2004Q1 2004Q2 2004Q3 2004Q4 2005Q1 2005Q2 2005Q3 2005Q4 2006Q1 2006Q2 2006Q3 42 Quarter 43 *Results from quadratic model 44 45 46 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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1 2 3 Appendix Figure 3. Standard Units Per Capita by Quarter 4 5 Cardiac Therapy (Hospital vs. Retail) 6 1000 7 8 9 10 900 11 For peer review only 12 13 800

14 15 16 700 17 18 19 600 http://bmjopen.bmj.com/ 20 21 Hospital Cardiac Therapy 22 500 23 Retail Cardiac Therapy 24 25 Hospital Regression Line 400 26 Retail Regression Line

27 on September 26, 2021 by guest. Protected copyright. Predicted Hospital Regression Line 28 29 300

30 Number Standardof Units per 1000people 31 32 200 33 34 35 100 36 37 38 0 39 40

41 1998Q2 1998Q3 1998Q4 1999Q1 1999Q2 1999Q3 1999Q4 2000Q1 2000Q2 2000Q3 2000Q4 2001Q1 2001Q2 2001Q3 2001Q4 2002Q1 2002Q2 2002Q3 2002Q4 2003Q1 2003Q2 2003Q3 2003Q4 2004Q1 2004Q2 2004Q3 2004Q4 2005Q1 2005Q2 2005Q3 2005Q4 2006Q1 2006Q2 2006Q3 42 Quarter 43 44 45 46 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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1 2 3 Appendix Figure 4. Standard Units Per Capita by Quarter 4 5 Lipid Regulating Agents (Hospital vs. Retail) 6 1800 7 8 9 10 1600 11 For peer review only 12 13 1400

14 15 16 17 1200 18 19 http://bmjopen.bmj.com/ 20 1000 21 22 Hospital Lipid Regulating Agents 23 Retail Lipid Regulating Agents 24 800 Hospital Regression Line* 25 26 Retail Regression Line 27 600 Predicted on September 26, 2021 by guest. Protected copyright. Hospital Regression Line 28 29

30 Number ofStandard Units per 1000people 31 400 32 33 34 200 35 36 37 0 38 39 40

41 1998Q2 1998Q3 1998Q4 1999Q1 1999Q2 1999Q3 1999Q4 2000Q1 2000Q2 2000Q3 2000Q4 2001Q1 2001Q2 2001Q3 2001Q4 2002Q1 2002Q2 2002Q3 2002Q4 2003Q1 2003Q2 2003Q3 2003Q4 2004Q1 2004Q2 2004Q3 2004Q4 2005Q1 2005Q2 2005Q3 2005Q4 2006Q1 2006Q2 2006Q3 42 Quarter *Results from quadratic model 43 44 45 46 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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1 2 3 Appendix Figure 5. Standard Units Per Capita by Quarter 4 5 Antihypertensives (Hospital vs. Retail) 6 7000 7 8 9 10 11 6000 For peer review only 12 13

14 15 5000 16 17 18 19 http://bmjopen.bmj.com/ 20 4000 21 22 Hospitial Antihypertensives 23 Retail Antihypertensives 24 3000 Hosptial Regression Line 25 26 Retail Regression Line 27 Predicted on September 26, 2021 by guest. Protected copyright. Hospital Regression Line 28 29 2000

30 Number Standardof Units per 1000people 31 32 33 1000 34 35 36 37 0 38 39 40

41 1998Q2 1998Q3 1998Q4 1999Q1 1999Q2 1999Q3 1999Q4 2000Q1 2000Q2 2000Q3 2000Q4 2001Q1 2001Q2 2001Q3 2001Q4 2002Q1 2002Q2 2002Q3 2002Q4 2003Q1 2003Q2 2003Q3 2003Q4 2004Q1 2004Q2 2004Q3 2004Q4 2005Q1 2005Q2 2005Q3 2005Q4 2006Q1 2006Q2 2006Q3 42 Quarter 43 44 45 46 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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1 2 3 Appendix Figure 6. Standard Units Per Capita by Quarter 4 5 Antineoplastics (Hospital vs. Retail) 6 60 7 8 9 10 11 For peer review only 12 50 13

14 15 16 17 40 18 19 http://bmjopen.bmj.com/ 20 21 Hospital Antineoplastics 22 30 23 Retail Antineoplastics 24 25 Hospital Regression Line 26 Retail Regression Line

27 on September 26, 2021 by guest. Protected copyright. 20 Predicted Hospital Regression Line 28 29

30 Number Standardof Units per 1000people 31 32 33 10 34 35 36 37 0

38 39 40

41 1998Q2 1998Q3 1998Q4 1999Q1 1999Q2 1999Q3 1999Q4 2000Q1 2000Q2 2000Q3 2000Q4 2001Q1 2001Q2 2001Q3 2001Q4 2002Q1 2002Q2 2002Q3 2002Q4 2003Q1 2003Q2 2003Q3 2003Q4 2004Q1 2004Q2 2004Q3 2004Q4 2005Q1 2005Q2 2005Q3 2005Q4 2006Q1 2006Q2 2006Q3 42 Quarter 43 44 45 46 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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1 2 3 Appendix Figure 7. Standard Units Per Capita by Quarter 4 5 Cytostatic Hormones (Hospital vs. Retail) 6 7 8 50 9 10 11 45 For peer review only 12 13 14 40

15 16 17 35 18 19 http://bmjopen.bmj.com/ 20 30 21 22 Hospital Cytostatic Hormones 23 25 24 Retail Cytostatic Hormones 25 Hospital Regression Line 26 20

27 Retail on September 26, 2021 by guest. Protected copyright. Regression Line 28 Predicted Hospital Regression Line 29 15 30

31 Number Standardof Units per 1000people 32 10 33 34 35 5 36 37 38 0

39 40

41 1998Q2 1998Q3 1998Q4 1999Q1 1999Q2 1999Q3 1999Q4 2000Q1 2000Q2 2000Q3 2000Q4 2001Q1 2001Q2 2001Q3 2001Q4 2002Q1 2002Q2 2002Q3 2002Q4 2003Q1 2003Q2 2003Q3 2003Q4 2004Q1 2004Q2 2004Q3 2004Q4 2005Q1 2005Q2 2005Q3 2005Q4 2006Q1 2006Q2 2006Q3 42 Quarter 43 44 45 46 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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1 2 3 Appendix Figure 8. Standard Units Per Capita by Quarter 4 5 Immunostimulating Agents (Hospital vs. Retail) 6 0.9 7 8 9 10 0.8 11 For peer review only 12 13 0.7

14 15 16 17 0.6 18 19 http://bmjopen.bmj.com/ 20 0.5 21 22 Hospital Immunostimulating Agents 23 Retail Immunostimulating Agents 24 0.4 * 25 Hospital Regression Line 26 Retail Regression Line

27 on September 26, 2021 by guest. Protected copyright. 0.3 Predicted Hospital Regression Line 28 29

30 Number Standardof Units per 1000people 31 0.2 32 33 34 0.1 35 36 37 38 0

39 40

41 1998Q2 1998Q3 1998Q4 1999Q1 1999Q2 1999Q3 1999Q4 2000Q1 2000Q2 2000Q3 2000Q4 2001Q1 2001Q2 2001Q3 2001Q4 2002Q1 2002Q2 2002Q3 2002Q4 2003Q1 2003Q2 2003Q3 2003Q4 2004Q1 2004Q2 2004Q3 2004Q4 2005Q1 2005Q2 2005Q3 2005Q4 2006Q1 2006Q2 2006Q3 42 Quarter 43 *Results from quadratic model 44 45 46 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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1 2 3 Appendix Figure 9. Licensing Status Market Share by Quarter 4 5 Insulin (Hospital Sector) 6 1.2 7 8 9 10 11 For peer review only 12 1 13 14 15 16 17 0.8 18 19 http://bmjopen.bmj.com/ Originator brand 20 21 Branded generic 22 0.6 Generic 23 24 GPO 25 Originator brand line* 26

27 on September 26, 2021 by guest. Protected copyright. Branded generic line 0.4 28 Generic line 29 30 ShareMarket (% ofstandard total units) GPO line 31 32 33 0.2 34 35 36 37 38 0

39 40

41 1998Q2 1998Q3 1998Q4 1999Q1 1999Q2 1999Q3 1999Q4 2000Q1 2000Q2 2000Q3 2000Q4 2001Q1 2001Q2 2001Q3 2001Q4 2002Q1 2002Q2 2002Q3 2002Q4 2003Q1 2003Q2 2003Q3 2003Q4 2004Q1 2004Q2 2004Q3 2004Q4 2005Q1 2005Q2 2005Q3 2005Q4 2006Q1 2006Q2 2006Q3 42 Quarter *Results from quadratic model 43 44 45 46 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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1 2 3 Appendix Figure 10. Licensing Status Market Share by Quarter 4 5 Antidiabetics (Hospital Sector) 6 0.7 7 8 9 10 11 0.6 For peer review only 12 13 14 15 0.5 16 17 18 19 http://bmjopen.bmj.com/ Originator brand 20 0.4 21 Branded generic 22 Generic 23 24 GPO 0.3 25 Originator brand line 26

27 on September 26, 2021 by guest. Protected copyright. Branded generic line 28 Generic line 29 0.2 30 ShareMarket (% ofstandard total units) GPO line 31 32 33 34 0.1 35 36 37 38 0 39 40

41 1998Q2 1998Q3 1998Q4 1999Q1 1999Q2 1999Q3 1999Q4 2000Q1 2000Q2 2000Q3 2000Q4 2001Q1 2001Q2 2001Q3 2001Q4 2002Q1 2002Q2 2002Q3 2002Q4 2003Q1 2003Q2 2003Q3 2003Q4 2004Q1 2004Q2 2004Q3 2004Q4 2005Q1 2005Q2 2005Q3 2005Q4 2006Q1 2006Q2 2006Q3 42 Quarter 43 44 45 46 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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1 2 3 Appendix Figure 11. Licensing Status Market Share by Quarter 4 5 Cardiac Therapy Agents (Hospital Sector) 6 0.9 7 8 9 10 0.8 11 For peer review only 12 13 0.7 14 15 16 17 0.6 18 19 http://bmjopen.bmj.com/ Originator brand 20 0.5 21 Branded generic 22 Generic 23 24 0.4 GPO 25 Originator brand line 26

27 on September 26, 2021 by guest. Protected copyright. Branded generic line* 0.3 28 Generic line 29 30 ShareMarket (% ofstandard total units) GPO line 31 0.2 32 33 34 0.1 35 36 37 38 0

39 40

41 1998Q2 1998Q3 1998Q4 1999Q1 1999Q2 1999Q3 1999Q4 2000Q1 2000Q2 2000Q3 2000Q4 2001Q1 2001Q2 2001Q3 2001Q4 2002Q1 2002Q2 2002Q3 2002Q4 2003Q1 2003Q2 2003Q3 2003Q4 2004Q1 2004Q2 2004Q3 2004Q4 2005Q1 2005Q2 2005Q3 2005Q4 2006Q1 2006Q2 2006Q3 42 Quarter 43 *Results from quadratic model 44 45 46 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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1 2 3 Appendix Figure 12. Licensing Status Market Share by Quarter 4 5 Lipid Regulating Agents (Hospital Sector) 6 0.9 7 8 9 10 0.8 11 For peer review only 12 13 0.7 14 15 16 17 0.6 18 19 http://bmjopen.bmj.com/ Originator brand 20 0.5 21 Branded generic 22 Generic 23 24 0.4 GPO 25 Originator brand line* 26

27 on September 26, 2021 by guest. Protected copyright. Branded generic line * 0.3 28 Generic line 29 30 GPO line 31 0.2 32 ShareMarket (% ofvolume total in standard units) 33 34 0.1 35 36 37 38 0

39 40

41 1998Q2 1998Q3 1998Q4 1999Q1 1999Q2 1999Q3 1999Q4 2000Q1 2000Q2 2000Q3 2000Q4 2001Q1 2001Q2 2001Q3 2001Q4 2002Q1 2002Q2 2002Q3 2002Q4 2003Q1 2003Q2 2003Q3 2003Q4 2004Q1 2004Q2 2004Q3 2004Q4 2005Q1 2005Q2 2005Q3 2005Q4 2006Q1 2006Q2 2006Q3 42 Quarter 43 *Results from quadratic model 44 45 46 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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1 2 3 Appendix Figure 13. Licensing Status Market Share by Quarter 4 5 Antihypertensives (Hospital Sector) 6 0.7 7 8 9 10 11 0.6 For peer review only 12 13 14 15 0.5 16 17 18 19 http://bmjopen.bmj.com/ Originator brand 20 0.4 21 Branded generic 22 Generic 23 24 GPO 0.3 25 Originator brand line* 26

27 on September 26, 2021 by guest. Protected copyright. Branded generic line* 28 Generic line 29 0.2 30 ShareMarket (% ofstandard total units) GPO line 31 32 33 0.1 34 35 36 37 38 0

39 40

41 1998Q2 1998Q3 1998Q4 1999Q1 1999Q2 1999Q3 1999Q4 2000Q1 2000Q2 2000Q3 2000Q4 2001Q1 2001Q2 2001Q3 2001Q4 2002Q1 2002Q2 2002Q3 2002Q4 2003Q1 2003Q2 2003Q3 2003Q4 2004Q1 2004Q2 2004Q3 2004Q4 2005Q1 2005Q2 2005Q3 2005Q4 2006Q1 2006Q2 2006Q3 42 Quarter 43 *Results from quadratic model 44 45 46 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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1 2 3 Appendix Figure 14. Licensing Status Market Share by Quarter 4 5 Antineoplastics (Hospital Sector) 6 0.7 7 8 9 10 11 0.6 For peer review only 12 13 14 15 0.5 16 17 18 19 http://bmjopen.bmj.com/ 20 0.4 21 Originator brand 22 Branded generic 23 24 Generic 0.3 25 Originator brand line 26

27 on September 26, 2021 by guest. Protected copyright. Branded generic line 28 Generic line 29 0.2 30 ShareMarket (% ofstandard total units) 31 32 33 34 0.1 35 36 37 38 0 39 40

41 1998Q2 1998Q3 1998Q4 1999Q1 1999Q2 1999Q3 1999Q4 2000Q1 2000Q2 2000Q3 2000Q4 2001Q1 2001Q2 2001Q3 2001Q4 2002Q1 2002Q2 2002Q3 2002Q4 2003Q1 2003Q2 2003Q3 2003Q4 2004Q1 2004Q2 2004Q3 2004Q4 2005Q1 2005Q2 2005Q3 2005Q4 2006Q1 2006Q2 2006Q3 42 Quarter 43 44 45 46 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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1 2 3 Appendix Figure 15. Licensing Status Market Share by Quarter 4 5 Cytostatic Hormones (Hospital Sector) 6 0.7 7 8 9 10 11 0.6 For peer review only 12 13 14 15 0.5 16 17 18 19 http://bmjopen.bmj.com/ 20 0.4 21 Originator brand 22 Branded generic 23 24 Generic 0.3 25 Originator brand line* 26

27 on September 26, 2021 by guest. Protected copyright. Branded generic line* 28 Generic line* 29 0.2 30 ShareMarket (% ofstandard total units) 31 32 33 0.1 34 35 36 37 38 0

39 40

41 1998Q2 1998Q3 1998Q4 1999Q1 1999Q2 1999Q3 1999Q4 2000Q1 2000Q2 2000Q3 2000Q4 2001Q1 2001Q2 2001Q3 2001Q4 2002Q1 2002Q2 2002Q3 2002Q4 2003Q1 2003Q2 2003Q3 2003Q4 2004Q1 2004Q2 2004Q3 2004Q4 2005Q1 2005Q2 2005Q3 2005Q4 2006Q1 2006Q2 2006Q3 42 Quarter 43 *Results from quadratic model 44 45 46 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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1 2 3 Appendix Figure 16. Licensing Status Market Share by Quarter 4 5 Immunostimulating Agents (Hospital Sector) 6 1.2 7 8 9 10 11 For peer review only 12 1 13 14 15 16 17 0.8 18 19 http://bmjopen.bmj.com/ 20 21 Originator brand 22 0.6 Branded generic 23 24 Generic 25 Originator brand line 26

27 on September 26, 2021 by guest. Protected copyright. Branded generic line 0.4 28 Generic line 29 30 ShareMarket (% ofstandard total units) 31 32 33 0.2 34 35 36 37 38 0 39 40

41 1998Q2 1998Q3 1998Q4 1999Q1 1999Q2 1999Q3 1999Q4 2000Q1 2000Q2 2000Q3 2000Q4 2001Q1 2001Q2 2001Q3 2001Q4 2002Q1 2002Q2 2002Q3 2002Q4 2003Q1 2003Q2 2003Q3 2003Q4 2004Q1 2004Q2 2004Q3 2004Q4 2005Q1 2005Q2 2005Q3 2005Q4 2006Q1 2006Q2 2006Q3 42 Quarter 43 44 45 46 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 50 of 52

1 2 3 STROBE Checklist: Impact of Universal Health Coverage in Thailand on Sales and Market BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from 4 5 Share of Medicines for Non-Communicable Diseases 6 7 8 STROBE Statement—checklist of items that should be included in reports of observational studies 9 10 Item 11 No Recommendation 12 13 Title and abstract 1 (a) Indicate the study’s design with a commonly used term in the title or the abstract 14 (b) Provide in the abstract an informative and balanced summary of what was done 15 and what was found 16 17 Introduction For peer review only 18 Background/rationale 2 Explain the scientific background and rationale for the investigation being reported 19 Objectives 3 State specific objectives, including any prespecified hypotheses 20 21 Methods 22 Study design 4 Present key elements of study design early in the paper 23 24 NOTE: We use an interrupted time series design, which is a robust longitudinal 25 observational design. 26 Setting 5 Describe the setting, locations, and relevant dates, including periods of recruitment, 27 28 exposure, follow-up, and data collection 29 Participants 6  (a) Cohort study—Give the eligibility criteria, and the sources and methods of 30 selection of participants. Describe methods of follow-up 31 Case-control study—Give the eligibility criteria, and the sources and methods of 32 33 case ascertainment and control selection. Give the rationale for the choice of cases 34 and controls 35 Cross-sectional study—Give the eligibility criteria, and the sources and methods of 36 37 selection of participants 38 (b) Cohort study—For matched studies, give matching criteria and number of http://bmjopen.bmj.com/ 39 exposed and unexposed 40 Case-control study—For matched studies, give matching criteria and the number of 41 42 controls per case 43 NOTE: We explain the data source and methods of selection (i.e., hospital vs. 44 pharmacy sales data – the latter serves as a non-equivalent comparison group) 45 46 and give the rationale for the choice of therapeutic classes and date range. 47 Variables 7 Clearly define all outcomes, exposures, predictors, potential confounders, and effect on September 26, 2021 by guest. Protected copyright. 48 modifiers. Give diagnostic criteria, if applicable 49 50 Data sources/ 8* For each variable of interest, give sources of data and details of methods of 51 measurement assessment (measurement). Describe comparability of assessment methods if there is 52 more than one group 53 Bias 9 Describe any efforts to address potential sources of bias 54 55 Study size 10 Explain how the study size was arrived at 56 Quantitative variables 11 Explain how quantitative variables were handled in the analyses. If applicable, 57 describe which groupings were chosen and why 58 59 Statistical methods 12 (a) Describe all statistical methods, including those used to control for confounding 60 (b) Describe any methods used to examine subgroups and interactions (c) Explain how missing data were addressed (d) Cohort study—If applicable, explain how loss to follow-up was addressed

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1 2 Case-control study—If applicable, explain how matching of cases and controls was

3 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from addressed 4 5 Cross-sectional study—If applicable, describe analytical methods taking account of 6 sampling strategy 7 (e) Describe any sensitivity analyses 8 9 Continued on next page 10 11 12 13 14 15 16 17 For peer review only 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 http://bmjopen.bmj.com/ 39 40 41 42 43 44 45 46 47 on September 26, 2021 by guest. Protected copyright. 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2

3 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from 4 Results 5 Participants 13*NA (a) Report numbers of individuals at each stage of study—eg numbers potentially eligible, 6 examined for eligibility, confirmed eligible, included in the study, completing follow-up, 7 8 and analysed 9 (b) Give reasons for non-participation at each stage 10 (c) Consider use of a flow diagram 11 12 Descriptive 14* (a) Give characteristics of study participants (eg demographic, clinical, social) and 13 data information on exposures and potential confounders 14 (b) Indicate number of participants with missing data for each variable of interest 15 16 (c) Cohort study—Summarise follow-up time (eg, average and total amount) 17 ForNOTE: peer We give the characteristics review of the therapeutic only classes (i.e., number subclasses, 18 medicines within each subclass). 19 Outcome data 15* Cohort study—Report numbers of outcome events or summary measures over time 20 21 Case-control study—Report numbers in each exposure category, or summary measures of 22 exposure 23 Cross-sectional study—Report numbers of outcome events or summary measures 24 25 NOTE: We report numbers of outcome events over time. 26 Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their 27 precision (eg, 95% confidence interval). Make clear which confounders were adjusted for 28 29 and why they were included 30 (b) Report category boundaries when continuous variables were categorized 31 (c) If relevant, consider translating estimates of relative risk into absolute risk for a 32 meaningful time period 33 34 Other analyses 17 Report other analyses done—eg analyses of subgroups and interactions, and sensitivity 35 analyses 36 37 Discussion 38 Key results 18 Summarise key results with reference to study objectives http://bmjopen.bmj.com/ 39 Limitations 19 Discuss limitations of the study, taking into account sources of potential bias or 40 41 imprecision. Discuss both direction and magnitude of any potential bias 42 Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, 43 multiplicity of analyses, results from similar studies, and other relevant evidence 44 45 Generalisability 21 Discuss the generalisability (external validity) of the study results 46 Other information 47 on September 26, 2021 by guest. Protected copyright. Funding 22 Give the source of funding and the role of the funders for the present study and, if 48 49 applicable, for the original study on which the present article is based 50 51 *Give information separately for cases and controls in case-control studies and, if applicable, for exposed and 52 53 unexposed groups in cohort and cross-sectional studies. 54 55 Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and 56 published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely 57 58 available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at 59 http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is 60 available at www.strobe-statement.org.

3 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

Impact of Universal Health Insurance Coverage in Thailand on Sales and Market Share of Medicines for Non- Communicable Diseases: An Interrupted Time Series Study

For peer review only Journal: BMJ Open

Manuscript ID: bmjopen-2012-001686.R1

Article Type: Research

Date Submitted by the Author: 04-Oct-2012

Complete List of Authors: Garabedian, Laura; Harvard Medical School and Harvard Pilgrim Health Care Institute, Department of Population Medicine Ross-Degnan, Dennis; Harvard Medical School and Harvard Pilgrim Health Care Institute, Department of Population Medicine Ratanawijitrasin, Sauwakon; Mahidol University, Faculty of Social Sciences and Humanities Stephens, Peter; IMS Health, Wagner, Anita; Harvard Medical School and Harvard Pilgrim Health Care Institute, Department of Population Medicine

Primary Subject Global health Heading:

Health policy, Health economics, Health services research, Pharmacology Secondary Subject Heading: http://bmjopen.bmj.com/ and therapeutics, Public health

Health policy < HEALTH SERVICES ADMINISTRATION & MANAGEMENT, Health economics < HEALTH SERVICES ADMINISTRATION & Keywords: MANAGEMENT, Essential Medicines, CARDIOLOGY, DIABETES & ENDOCRINOLOGY, ONCOLOGY

on September 26, 2021 by guest. Protected copyright.

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1 2 3 1 TITLE PAGE 4 5 2 6 3 Impact of Universal Health Insurance Coverage in Thailand on Sales and Market Share of 7 4 Medicines for Non-Communicable Diseases: an Interrupted Time Series Study 8 5 9 6 Laura Faden Garabedian, MPH1, Dennis Ross-Degnan, ScD1, Sauwakon Ratanawijitrasin, PhD2, 10 3 1 11 7 Peter Stephens, MA , Anita Wagner, PharmD, MPH, DrPH 12 8 13 9 Institutions: 14 10 1 Drug Policy Research Group and WHO Collaborating Center in Pharmaceutical Policy 15 11 Department of PopulationFor Medicine,peer Harvard review Medical School andonly Harvard Pilgrim Health Care 16 12 Institute 17 18 13 133 Brookline Ave., Sixth Floor 19 14 Boston, MA, USA 20 15 21 16 Dennis Ross-Degnan and Anita Wagner are Associate Professors. Laura Faden Garabedian is a 22 17 Research Fellow and PhD Candidate. 23 24 18 25 19 Corresponding author: Laura Faden Garabedian 26 20 Phone: +1 617 509 9921 27 21 Email: [email protected] 28 22 29 2 30 23 Professor 31 24 Faculty of Social Sciences and Humanities, Mahidol University 32 25 Salaya, Buddhamonthon, Nakhonpathom, 73170 Thailand 33 26 3 34 27 Director, Public Health Affairs http://bmjopen.bmj.com/ 35 28 IMS Health 36 37 29 7 Harewood Avenue 38 30 London, NW1 6JB, UK 39 31 40 32 Study Design: Observational study (interrupted time series design) 41 33 42 on September 26, 2021 by guest. Protected copyright. 43 34 Acknowledgements: We gratefully acknowledge support of statistical analyses by Dr. Fang 44 35 Zhang, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim 45 36 Health Care Institute, Boston, USA. Dr. Sanita Hirunrassamee, Phramongkutklao Hospital, 46 37 Bangkok, Thailand, and Ms. Rosarin Sruamsiri and Dr. Nathorn Chaiyakunapruk, Naresuan 47 38 University, Phitsanulok, Thailand, provided helpful input on Thai essential medicines listings 48 39 and coverage policies. Mr. Amit Backliwal, at the time of the study at IMS Health, Bangkok, 49 50 40 Thailand, shared valuable insights on the Thai pharmaceutical market. 51 41 52 42 Author contributions: Laura Garabedian, Dennis Ross-Degnan and Anita Wagner designed the 53 43 study and developed the analytic approach. Peter Stephens assembled the data files. Laura 54 44 Garabedian analyzed the data. Sauwakon Ratanawijitrasin provided the Thai national list of 55 56 45 essential medicines and information on relevant Thai policies and context surrounding the 57 58 59 60 1 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 58 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 1 reform. All authors participated in the interpretation of the results. Laura Garabedian wrote the 4 5 2 first draft of the paper. All authors contributed to the writing of the manuscript. 6 3 7 4 Opinions expressed are solely those of the authors and not of the institutions they represent. 8 5 9 6 Competing Interest Statement: All authors have completed the Unified Competing Interest 10 11 7 form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) 12 8 and declare: LFG had financial support from Harvard Medical School and Harvard University, 13 9 AW and DRD were supported in part by a grant from the Novartis Foundation for Sustainable 14 10 Development, PS is an employee of IMS Health; no financial relationships with any 15 11 organisations thatFor might have peer an interest inreview the submitted work inonly the previous 3 years; no other 16 12 relationships or activities that could appear to have influenced the submitted work. 17 18 19 13 Funding: IMS Health provided the data in-kind. The Harvard Medical School Fellowship in 20 14 Pharmaceutical Policy Research and the Harvard University PhD Program in Health Policy 21 15 supported Ms. Garabedian. Drs. Wagner and Ross-Degnan were supported in part by a grant 22 16 from the Novartis Foundation for Sustainable Development to develop examples of research on 23 17 access to medicines using IMS Health data for presentation at the Third International Conference 24 18 for Improving Use of Medicines. 25 26 19 27 20 IRB Approval: Harvard Pilgrim Health Care Institute Office of Sponsored Programs 28 21 29 22 Exclusive Licence Statement: The Corresponding Author has the right to grant on behalf of all 30 23 authors and does grant on behalf of all authors, a worldwide licence to the Publishers and its 31 32 24 licensees in perpetuity, in all forms, formats and media (whether known now or created in the 33 25 future), to i) publish, reproduce, distribute, display and store the Contribution, ii) translate the

34 26 Contribution into other languages, create adaptations, reprints, include within collections and http://bmjopen.bmj.com/ 35 27 create summaries, extracts and/or, abstracts of the Contribution, iii) create any other derivative 36 28 work(s) based on the Contribution, iv) to exploit all subsidiary rights in the Contribution, v) the 37 29 inclusion of electronic links from the Contribution to third party material where-ever it may be 38 39 30 located; and, vi) licence any third party to do any or all of the above. 40 31 41 32 Data Sharing Statement: Data available upon request, at the approval of IMS Institute for 42 33 Healthcare Informatics. on September 26, 2021 by guest. Protected copyright. 43 44 34 45 46 35 47 48 36 49 50 37 51 52 38 53 54 39 55 56 40 57 58 59 60 2 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 58 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 1 Article Summary 4 5 2 Article Focus 6 7 8 3 • Medicines present a key challenge to achieving universal coverage. 9 4 • Health insurance systems have the potential to improve cost-effective use of medicines, 10 5 yet there is little evidence about their impact on medicine use in low- and middle-income 11 6 countries. 12 7 • The rapid implementation of universal health coverage in Thailand presents a unique 13 14 8 opportunity to measure the impact of health insurance expansion and capitated payment 15 9 on utilizationFor of medicines. peer review only 16 17 10 Key Messages 18 19 11 • Expanding health insurance coverage with a medicines benefit to the entire Thai 20 12 population increased access to medicines in primary care. 21 13 • The universal coverage scheme did not seem to have increased use of medicines for 22 23 14 diseases that are typically treated in secondary or tertiary care settings, or increased 24 15 generic market penetration. 25 16 • In the future, it will be important for countries to assess quality and equity of medicines 26 17 use as they pursue policies to achieve universal coverage. 27 28 18 Strengths and Limitations 29 30 19 • We used an interrupted time series design, the strongest quasi-experimental approach for 31 32 20 evaluating effects of interventions, increasing internal validity. 33 21 • It is impossible to examine population subgroups in national IMS Health market data, but

34 22 we are reasonably confident that universal coverage scheme enrollees are responsible for http://bmjopen.bmj.com/ 35 23 observed changes. 36 37 24 38 39 25 40 41 26 42 on September 26, 2021 by guest. Protected copyright. 43 27 44 45 28 46 47 29 48 49 30 50 51 52 31 53 54 32 55 56 33 57 58 34 59 60 3 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 58 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 1 ABSTRACT 4 5 2 Objective: In 2001, Thailand implemented the Universal Coverage Scheme (UCS), a public 6 7 3 insurance system that aimed to achieve universal access to health care, including essential 8 9 4 medicines, and to influence primary care centers and hospitals to use resources efficiently, via 10 11 5 capitated payment for outpatient services and other payment policies for inpatient care. Our 12 13 6 objective was to evaluate the impact of the UCS on utilization of medicines in Thailand for three 14 7 non-communicable diseases: cancer, cardiovascular disease, and diabetes. 15 For peer review only 16 8 Design: Interrupted time series design, with a non-equivalent comparison group. 17 18 9 Setting: Thailand, 1998-2006. 19 20 10 Data: Quarterly purchases of medicines from hospital and retail pharmacies collected by IMS 21 11 Health between 1998 and 2006. 22 23 12 Intervention: UCS implementation, April-October 2001. 24 25 13 Outcome measures: Total pharmaceutical sales volume and percent market share by licensing 26 27 14 status and National Essential Medicine List (NEML) status. 28 29 15 Results: The UCS was associated with long-term increases in sales of medicines for conditions 30 16 that are typically treated in outpatient primary care settings, such as diabetes, high cholesterol 31 32 17 and high blood pressure, but not for medicines for diseases that are typically treated in secondary 33

34 18 or tertiary care settings, such as heart failure, arrhythmias, and cancer. While the majority of http://bmjopen.bmj.com/ 35 36 19 increases in sales were for essential medicines, there were also post-policy increases in sales of 37 20 non-essential medicines. Immediately following the reform, there was a significant shift in 38 39 21 hospital sector market share by licensing status for most classes of medicines. Government- 40 41 22 produced products often replaced branded generic or generic competitors. 42 on September 26, 2021 by guest. Protected copyright. 43 23 Conclusions: Our results suggest that expanding health insurance coverage with a medicines 44 45 24 benefit to the entire Thai population increased access to medicines in primary care. However, our 46 25 study also suggests that the UCS may have had potentially undesirable effects. Evaluations of the 47 48 26 long-term impacts of universal health coverage on medicines utilization are urgently needed. 49 50 51 27 52 28 53 54 55 56 57 58 59 60 4 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 58 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 1 MANUSCRIPT 4 5 6 2 Introduction 7 8 3 Universal Health Coverage 9 10 4 In 2005, Member States of the World Health Organization (WHO) made a commitment to work 11 5 towards universal health care coverage.1 The 2010 WHO World Health Report provides a 12 13 6 roadmap for countries to achieve this goal.2 Universal coverage requires the restructuring of 14 15 7 health care and financingFor systems peer to improve review access to health care only services, reduce financial 16 2 17 8 hardship, and increase the efficiency and equity of the health system. 18 9 19 20 10 Medicines, which consume 25%–65% of total public and private spending on health in 21 22 11 developing countries,3 present a key challenge to achieving universal coverage. The high 23 24 12 spending on, and inefficient use of, medicines threaten the financial sustainability of a universal 25 26 13 coverage scheme. According to the WHO, three of the top ten sources of health care inefficiency 27 14 involve medicines: high medicine prices and underuse of generics; use of substandard and 28 29 15 counterfeit medicines; and inappropriate and ineffective use of medicines.2 Health insurance 30 31 16 systems have several features (e.g., a defined population, access to utilization data, and financial 32 33 17 leverage) that give them a unique advantage to reduce out-of-pocket (OOP) expenditures and

34 18 improve the cost-effective use of medicines through active management strategies involving http://bmjopen.bmj.com/ 35 36 19 medicines selection, purchasing, contracting (e.g., physician payment) and utilization 37 38 20 management.4 However, there is little evidence about the impact of health insurance on access to 39 4 40 21 and use of medicines in low- and middle-income countries (LMICs). 41 42 22 on September 26, 2021 by guest. Protected copyright. 43 23 The recent implementation of universal health coverage in Thailand presents a unique 44 45 24 opportunity to measure the impact of health insurance expansion and hospital payment changes 46 5 47 25 (the majority of the population is now covered under a closed-ended payment scheme ) on 48 49 26 utilization of medicines. 50 27 51 52 28 Universal Health Coverage in Thailand 53 54 29 With the implementation of the UCS in 2001, Thailand became one of the first LMICs to achieve 55 6,7 56 30 universal coverage. The reform preserved the formal sector workforce schemes: the Social 57 58 31 Health Insurance (SHI) scheme for private sector employees (7·2% of the total population in 59 60 5 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 58 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 1 2001) and the Civil Service Medical Benefit Scheme (CSMBS) for government employees and 4 5 2 their dependents (8·5%).8 The UCS covered those previously enrolled in a voluntary health card 6 7 3 (VHC) scheme (20·8%), in private health insurance (2·1%), or in a tax-based, means-tested Low 8 8,9 9 4 Income Scheme (LIS) for the poor, elderly, children and disabled (32·4%) as well as more than 10 8 11 5 one quarter (29·0%) of the population without previous insurance. The UCS was rolled out to all 12 6 provinces between April and October 2001.6 By 2004, 95·5% of the population was insured, with 13 14 7 three-quarters (75.2%) of the population covered by the UCS.6 15 For peer review only 16 8 17 18 9 In addition to coverage expansion, the reform also dramatically altered the mechanism for 19 10 hospital payment. Before the reform, hospitals were accustomed to fee-for-service (FFS) 20 21 11 payments from most insurance schemes, aside from SSI, and the uninsured, who paid OOP per 22 10 11 23 12 service (i.e., user fees). The majority of user fee spending was on medicines. After the 24 25 13 reform, FFS payment only applied to CSMBS patients and for the majority of patients, now UCS 26 14 enrollees, hospitals were paid on a closed-ended basis5 for all covered services, including 27 28 15 medicines. 29 30 16 31 32 17 The UCS is a compulsory, tax-financed scheme with comprehensive coverage of inpatient and 33 18 outpatient services, including medicines on the National List of Essential Medicines (NLEM).6 34 http://bmjopen.bmj.com/ 35 19 Individuals must enroll in the scheme at a local Contracting Unit for Primary Care (CUP),6 36 37 20 primarily housed in government-owned hospitals.12 Each CUP receives a capitated payment per 38 6 39 21 registered member to provide outpatient services and medicines. CUPs initially served as gate- 40 41 22 keepers for secondary and tertiary hospitals. At the beginning of the scheme, when patients were 42 23 referred, diagnosis-related payments (DRG) for higher-level care had to come out of the CUP’s on September 26, 2021 by guest. Protected copyright. 43 44 24 capitated payment, so CUPs had a financial disincentive to refer patients.6 Shortly after the 45 46 25 reform was implemented, a separate fund (i.e., a global budget) for inpatient services was 47 6 48 26 created, which likely reduced disincentives to refer created by the capitated payment scheme. A 49 50 27 capitated payment also creates financial incentives for use of lower cost medicines (e.g., generics 51 28 or less expensive therapeutic alternatives). 52 53 29 54 55 30 Our objective was to evaluate the immediate, short-term (one year) and long-term (five year) 56 57 31 impacts of the UCS on pharmaceutical market size and composition for medicines for three non- 58 59 60 6 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 58 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 1 communicable diseases (NCDs): cancer, cardiovascular disease, and diabetes. We hypothesized 4 5 2 that the UCS would result in a gradual increase in sales volume, particularly of products used in 6 7 3 primary care, as enrollment into the scheme increased and likely made access to health services 8 9 4 and medicines more affordable for the majority of the population. We also hypothesized that 10 11 5 there would be an immediate shift in market share from more expensive brand name to less 12 6 expensive generic or branded generic products and to medicines on the NLEM in response to 13 14 7 closed-ended budget rules. We focused on medicines for NCDs since these illnesses represent a 15 For peer review13–16 only17 16 8 large and growing health care burden in Thailand and other LMICs and most, but not all, 17 18 9 medicines for NCDs would be prescribed and dispensed in primary care settings. 19 20 10 Methods 21 22 11 Data 23 24 12 We used data on quarterly pharmaceutical sales in Thailand from 1998 to 2006 provided by IMS 25 18 26 13 Health. The sales data are generated from reports to IMS Health by multinational 27 14 pharmaceutical companies and surveys of purchases by hospital and retail pharmacies. IMS 28 29 15 surveys approximately 200 hospitals (including general and specialized, public and private) and 30 31 16 350 retail pharmacies in Thailand. These facilities constitute a stratified random sample of the 32 33 17 over 1,100 hospitals and 14,000 retail pharmacies in Thailand to enable national projections.

34 18 Documentation on the IMS data collection and validation process is available upon request from http://bmjopen.bmj.com/ 35 36 19 the authors. Medicines were classified according to the European Pharmaceutical Research 37 38 20 Association (EphMRA) Anatomical Therapeutic Chemical (ATC) system.19 39 40 21 41 42 22 Outcomes on September 26, 2021 by guest. Protected copyright. 43 23 We used two outcome measures: total volume and percent market share. Total volume is the 44 45 24 number of standard units purchased per capita per quarter (i.e., “sales”). We analyzed total 46 47 25 volume by sector (i.e., retail versus hospital). A standard unit, as defined by IMS Health, is the 48 49 26 smallest dose of a product, which equates to one tablet or capsule for an oral dosage form, one 50 27 teaspoon (5ml) for a syrup, and one ampoule or vial for an injectable product. For the total 51 52 28 volume analyses, we divided total volume by size of the population over 15 years old to control 53 54 29 for population growth (using yearly population estimates from the World Bank20). We used the 55 56 30 entire population as denominator for insulins, since they are also used for Type 1 diabetes, a 57 58 31 chronic disease that affects children. Percent market share is the percent of total volume in four 59 60 7 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 58 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 1 mutually exclusive categories of licensing status: originator brand products, branded generic 4 5 2 products (products sold under a brand name other than the originator brand name of the 6 7 3 molecule), generic products (products that are sold under the generic molecule name), and 8 9 4 products manufactured by Thailand’s Government Pharmaceutical Organization (GPO). We also 10 11 5 assessed percent market share by NLEM status (based on the 1999 and 2004 Thai NLEM). 12 6 13 14 7 We analyzed total volume and market share for medicines in eight therapeutic classes: two 15 For peer review only 16 8 classes of diabetes products (oral antidiabetics and insulins), three classes of cardiovascular 17 18 9 disease products (antihypertensives, lipid-regulating, and cardiac therapy products) and three 19 10 classes of cancer products (antineoplastics, immunostimulating agents, and cytostatic hormone 20 21 11 therapy products); Table 1 in the online appendix lists all medicines by ATC code. We assigned 22 23 12 each therapeutic class to one of two categories: medicines usually used to treat primary care 24 25 13 health conditions and medicines usually used to treat more complicated conditions, typically in 26 14 secondary/tertiary, often inpatient care, settings. Antidiabetic, insulin, antihypertensive and lipid- 27 28 15 lowering products are usually used for primary care conditions (i.e., diabetes, high blood 29 30 16 pressure and high cholesterol), whereas cardiac therapy and cancer products are usually used for 31 32 17 more severe conditions that more likely require treatment by a specialist and/or in an inpatient 33 18 setting. 34 http://bmjopen.bmj.com/ 35 19 36 37 20 Research Design 38 39 21 We used an interrupted time series design, the strongest quasi-experimental approach for 40 41 22 evaluating effects of interventions, which has been used extensively for medication use 42 21 23 research. Although we did not have an equivalent control group, we used medicines sold in the on September 26, 2021 by guest. Protected copyright. 43 44 24 retail sector as a non-equivalent comparison group,22 assuming that the retail market should be 45 46 25 relatively unaffected by the reforms since UCS enrollees could only obtain covered medicines 47 48 26 through their local, hospital-based CUP. 49 50 27 51 28 Statistical Analysis 52 53 29 The intervention was the UCS roll-out from April to October 2001. We defined three distinct 54 55 30 periods: 12 quarters pre-reform (1998Q2-2001Q1), a 3-quarter UCS roll-out period (2001Q2- 56 57 31 2001Q4; grey box in figures), and 19 quarters post-reform (2002Q1-2006Q3). We ended analysis 58 59 60 8 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 58 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 1 prior to 2006Q4 since there was a policy change at that time (the removal of an initial 30 Baht 4 5 2 co-payment per visit) which may have impacted outcomes. In sensitivity analyses, we extended 6 7 3 the intervention roll-out period through 2002 and through 2003 to account for potentially delayed 8 9 4 implementation and lag of actual enrollment into the scheme. 10 11 5 12 6 We used segmented linear regression to measure the pre-reform trend, the immediate level 13 14 7 change following the intervention period, and the post-reform change in trend (as compared to 15 For peer review only 16 8 the pre-reform trend). For the NLEM analysis, we reclassified NLEM status in 2005Q1 (when 17 18 9 the 2004 list was implemented) and included a pre-post term (“NLEM”) in the model to account 19 10 for possible discontinuity due to the reclassification. We report two estimates from the 20 21 11 segmented regression models – the post-reform change in trend and the immediate level change 22 23 12 following the reform. We controlled for serial autocorrelation using an autoregressive error 24 25 13 model. We retained all terms in the models, even if non-significant. We used the models to 26 14 estimate absolute and relative differences (with 95% confidence intervals)23 in observed versus 27 28 15 predicted total volume at one year and five years post-reform. In sensitivity analyses, we 29 30 16 included a quadratic term for the post-reform trend and used a likelihood ratio test to determine 31 32 17 the best-fitting model. We report below results from the best-fitting model of the shortest (i.e., 3 33 18 quarter) intervention period and mention differences in model results where they existed. Results 34 http://bmjopen.bmj.com/ 35 19 from sensitivity analyses are available upon request. We used the AUTOREG procedure in SAS 36 37 20 9.3 for all analyses. 38 39 21 40 41 42 22 Results on September 26, 2021 by guest. Protected copyright. 43 23 44 45 24 Hospital Sector Volume 46 47 25 The majority of sales in Thailand for all cancer, cardiovascular disease and diabetes medicines 48 49 26 studied were in the hospital sector and were for medicines on the NLEM. After implementation 50 27 of the UCS, there was a significant increase in level of sales of insulins and a significant increase 51 52 28 in trend in sales of antidiabetic, insulin, antihypertensive, lipid regulating, and cytostatic 53 54 29 hormone products [Table 1, Figures 1 and 2]. There was a significant reduction in level of sales 55 56 30 immediately following the reforms for three medication classes: antihypertensive, cardiac 57 58 59 60 9 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 58 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 1 therapy and immunostimulating agents (although only the latter was significant in the sensitivity 4 5 2 analyses using a longer intervention period) [Table 1, Figures 1 and 2]. 6 7 3 8 9 4 The UCS was associated with increased sales of diabetes medicines. One year after the policy, 10 11 5 the sale of insulin was 35% (95% CI: 15%, 55%) higher and, at five years, 174% (95% CI: 12 6 114%-235%) higher than what would have been expected in the absence of the UCS [Table 2]. 13 14 7 The increase in insulin sales was driven primarily by human insulins, which are on the NLEM 15 For peer review only 16 8 and marketed as branded generics by two manufacturers. The policy was associated with a 39% 17 18 9 (95% CI: 14%, 64%) increase in antidiabetic product sales five years after implementation 19 10 [Table 2]. This was largely due to increased sales of generic and branded generic metformin and 20 21 11 glibenclamide products, both of which are on the NLEM. 22 23 12 24 25 13 Implementation of the UCS appears to have had a mixed impact on sales of cardiovascular 26 14 medicines. Five years after the policy, the sale of lipid lowering agents was nearly double (108% 27 28 15 increase; 95% CI: 60%, 157%) what would have been expected in the absence of the scheme 29 30 16 [Table 2]. The increase was primarily due to sales of branded generic simvastatin and 31 32 17 gemfibrozil products, which are on the NLEM, and a small but steady increase in sales of 33 18 originator atorvastatin products, which were not on the NLEM until 2004. For antihypertensives, 34 http://bmjopen.bmj.com/ 35 19 the significant increase in post-policy trend compensated for an initial drop in sales, resulting in a 36 37 20 slight increase in sales five years after the policy (19% increase; 95% CI: -3%, 40%). The 38 39 21 increased trend was primarily due to sales of enalapril, atenolol, and amlodipine, all of which are 40 41 22 on the NLEM and predominately sold as branded generics. The reform had no significant impact 42 23 on sales of cardiac therapy medicines one or five years after the policy. on September 26, 2021 by guest. Protected copyright. 43 44 24 45 46 25 The results were also mixed for cancer medicines. The UCS had no significant one- or five-year 47 48 26 impact on the sale of antineoplastics or cytostatic hormones (although the latter class did 49 50 27 experience a significant post-policy increase in trend). However, the policy was associated with 51 28 an immediate reduction in sales of immunostimulating agents that did not recover in the post- 52 53 29 policy period. One year after implementation, the sale of immunostimulating agents was 35% 54 55 30 (95% CI: -45%, -25%) lower than expected from pre-policy trends, and 26% lower (95% CI: - 56 57 31 45%, -8%) five years post-policy. This drop is almost entirely due to a sharp reduction in sales of 58 59 60 10 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 58 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 1 interferon alfa-2b, a non-NLEM medicine, around the time of UCS implementation, which could 4 5 2 have been due to a coincidental recall of an interferon alfa-2b product.24 6 7 3 8 9 4 Finally, as expected, the reform had little impact on sales volume in the retail sector – there were 10 11 5 few significant post-implementation changes, and the changes that were significant were small in 12 6 magnitude [see online appendix, Table 2]. 13 14 7 15 For peer review only 16 8 Hospital Sector Market Share 17 18 9 Immediately following the reform, there were significant shifts in hospital sector market share by 19 10 licensing status for most classes [Table 3]. The changes for antidiabetics and cardiac medicines - 20 21 11 the two therapeutic classes with the largest shifts – were due to significant increases in GPO- 22 23 12 produced medicines, primarily at the expense of branded generics and, to a lesser extent, 24 25 13 generics. There was a significant increase in GPO antidiabetic products (+16% of market; 95% 26 14 CI: 12%, 20%), and decreases in branded generic (-12%; 95% CI:-16%, -9%) and generic (-4%; 27 28 15 95% CI: -6%,-1%) products immediately after the policy [Figure 3]. Similarly, there was a 29 30 16 significant increase in GPO cardiac therapy products (+22%; 95% CI: 15%, 28%), and 31 32 17 significant decreases of branded generic (-14%; 95% CI:-21%, -7%) and generic (-4%; 95% CI:- 33 18 6%, -2%) products immediately after the policy [Figure 4]. There was also a small decrease in 34 http://bmjopen.bmj.com/ 35 19 market share of generic antihypertensives (-6%; 95% CI: -8%, -3%), which was compensated for 36 37 20 by a marginally significant increase in GPO products. 38 39 21 40 41 22 The market for lipid regulating agents experienced an immediate shift from originator products (- 42 23 8% market share; 95% CI:-10%, -5%) to branded generics (+8%; 95% CI:5%, 10%). A similar on September 26, 2021 by guest. Protected copyright. 43 44 24 shift was seen for in the market for immunostimulating agents (6% decrease in originator 45 46 25 products [95% CI:-10%, -3%] and a 5% increase in branded generics [95% CI:2%, 7%]). The 47 48 26 cytostatic hormone market experienced an immediate shift from branded generic (-8%; 95% CI:- 49 50 27 12%, -4%) to generic products (+6%, 95% CI: 1%, 11%). Generic insulins experienced a slight 51 28 decrease in market share caused by the market exit of the sole generic manufacturer just prior to 52 53 29 the policy. There were no immediate changes in market share for antineoplastics. Aside from the 54 55 30 immediate level changes following the policy, there were few major changes in market share for 56 57 31 all classes. 58 59 60 11 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 58 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 1 The UCS did not have a major impact on NLEM market share, likely because the share of 4 5 2 NLEM medicines was already quite high [see online appendix Table 6 and Figure 17]. The only 6 7 3 notable level change, for immunostimulating agents, was likely due to the coincidental recall of a 8 24 9 4 non-NLEM interferon alfa-2b product. While all medicine classes had significant post-reform 10 11 5 trends, these trends were small in magnitude and NLEM market share remained fairly stable over 12 6 the study period until the 2004 NLEM was introduced. There were large changes in NLEM 13 14 7 market share for three classes – antihypertensives, lipid regulating agents and cytostatic 15 For peer review only 16 8 hormones – at the time of the 2004 NLEM implementation in 2005Q1 [see online appendix 17 18 9 Table 6 and Figure 17]. Given the increase in post-reform volume for many medicine classes, a 19 10 stable NLEM market share in the short-term (i.e., pre-2005) following the UCS implementation 20 21 11 suggests a post-reform increase in both NLEM and non-NLEM medicines. 22 23 12 24 25 13 Discussion 26 14 The UCS was associated with long-term (i.e., 5 year) increases in hospital sector sales of 27 28 15 medicines for chronic diseases that are usually treated in primary care settings, such as diabetes, 29 30 16 high blood pressure, and high cholesterol. We hypothesized this gradual increase in volumes 31 25 32 17 since the UCS expanded access to primary care and actual enrollment into the scheme occurred 33 18 gradually from implementation in 2001 until around 2004, by which time 95·5% of the 34 http://bmjopen.bmj.com/ 35 19 population had insurance coverage.6 The UCS, which radically changed hospital financing and 36 37 20 reimbursement, was also associated with an immediate market shift to locally produced or 38 39 21 branded generic products for most therapeutic classes. 40 41 22 42 23 Despite these increases in access, the policy did not appear to increase sales of medicines for on September 26, 2021 by guest. Protected copyright. 43 44 24 more severe diseases like heart failure, arrhythmias, and cancer, which are often treated in 45 46 25 secondary or tertiary settings. This finding is consistent with evidence that the capitated payment 47 6,25,26 48 26 system initially discouraged referrals of UCS patients to higher-level care. The UCS also 49 50 27 appears to have had a mixed impact on utilization of essential medicines. There were increases in 51 28 NLEM medicines, which are covered, as well as non-NLEM medicines. Similarly, given the 52 53 29 capitated UCS payment system, we expected to see an increase in sales of generic medicines, 54 55 30 which are typically less expensive. However, the majority of sales in most classes were for 56 57 31 branded generic products, many of which had generic alternatives in the market. Interestingly, 58 59 60 12 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 58 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 1 substantial market share shifts occurred toward products manufactured by the Thai GPO, which 4 5 2 have been noted to have higher than market prices.27 By law, GPO products received preferential 6 7 3 status by hospital purchasers,28 which negates the incentive to prescribe cheaper alternatives 8 9 4 under the capitated payment system. While the increase in GPO products and the UCS 10 11 5 implementation may be a coincidence in timing, it is noteworthy that the GPO expanded its 12 6 product line at a time when the UCS policy expanded the market of people who could afford 13 14 7 medicines. 15 For peer review only 16 8 17 18 9 Our study demonstrates the value of IMS Health market intelligence data for rigorous health 19 10 policy evaluation. Unlike other sources of data on pharmaceutical utilization (i.e., national health 20 21 11 surveys or ad hoc hospital surveys), IMS data represent country pharmaceutical markets 22 23 12 consistently over time and are useful for the evaluation of system-wide interventions. 24 25 13 Nevertheless, the data pose some limitations. Aggregate national sales data do not allow us to 26 14 determine whether observed increases in medicines sales occurred preferentially among UCS 27 28 15 enrollees or enrollees in the SHI and CSMBS schemes, conceivably to compensate for financial 29 30 16 strain of the UCS on hospital budgets.6 CSMBS expenditures increased following UCS 31 29 32 17 implementation and increased medicines sales among CSMBS enrollees, reimbursed on a fee- 33 18 for-service basis, could explain increases in non-NLEM medicines and medicines with less 34 http://bmjopen.bmj.com/ 35 19 expensive therapeutic alternatives.5 However, it is unlikely that increased utilization among 36 37 20 CSMBS enrollees explains most of the observed volume changes since this would imply that 38 39 21 one-half (for diabetes) to three-quarters (for hypertension) of CSMBS members (7.1% of the 40 6 41 22 total population in 2004 ) were on these treatments in 2004. Even the CSMBS and SSI schemes 42 6 23 combined (20.3% of the total population in 2004 ) are unlikely to be responsible for the observed on September 26, 2021 by guest. Protected copyright. 43 44 24 changes since this would imply that one-quarter (for diabetes) and one-third (for hypertension) of 45 46 25 enrollees in the two schemes were on these treatments in 2004. These estimates are much higher 47 30 31 48 26 than the national prevalence (6.7% for diabetes and 22.0% for hypertension in 2004) and 49 50 27 unlikely in the civil servant and private sector workforce populations, which are likely to be 51 28 healthier and wealthier than the national average. 52 53 29 54 55 30 Our interpretation of the observed changes assumes that pharmaceutical sales to hospital and 56 57 31 retail pharmacies reflected total market utilization, and that hospital sales volumes included 58 59 60 13 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 58 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 1 utilization at affiliated primary care units. This assumption seems justified in light of the 4 5 2 estimated 91% accuracy of IMS Health data in representing the Thai pharmaceutical market.32 6 7 3 For local generic products, including those produced by the GPO, IMS Health data are based on 8 9 4 pharmacy surveys only (as opposed to pharmacy surveys and manufacturer reports), so we may 10 11 5 have underestimated utilization. However, unless this systematic underestimation changed at the 12 6 point of the UCS implementation, it would not have impacted our results. Finally, since we did 13 14 7 not convert standard units of product sold to defined daily doses (DDD), we do not describe sales 15 For peer review only 16 8 changes in terms of average adult doses. 17 18 9 19 10 There are also potential limitations due to study design and statistical analysis. We addressed the 20 21 11 main threat to the internal validity of the interrupted time series design – a concurrent event that 22 23 12 affects the outcome of interest – by assessing other policies or market events that occurred at the 24 25 13 time of the UCS, through literature reviews, discussions with in-country experts, and by 26 14 including the retail sector as a comparison. The statistical approach, segmented regression 27 28 15 analysis, usually assumes a linear trend and well-defined break point. Sensitivity analyses that 29 30 16 varied model specification and intervention duration did not change the findings. By reporting 31 32 17 results from fully-specified models, we may have underestimated the statistical significance of 33 18 one- and five-year change estimates. 34 http://bmjopen.bmj.com/ 35 19 36 37 20 While both the context and the implementation of universal coverage in Thailand are unique and 38 39 21 not necessarily generalizable to other LMICs, our findings suggest that expanding health 40 41 22 insurance coverage with a medicines benefit to the entire population, together with changes in 42 23 the payment system and increased local manufacturing, increased the per capita volume of on September 26, 2021 by guest. Protected copyright. 43 44 24 medicines sold and, by inference, improved access to medicines in the primary care sector in 45 46 25 Thailand, presumably by making medicines more affordable. Since the study period, Thailand 47 48 26 has enacted further policies to address pharmaceutical sector cost escalation (e.g., strict 49 33 50 27 enforcement of reimbursement for only NLEM medicines in the CSMBS ) and to ensure 51 28 appropriate access to non-NLEM medicines (e.g., coverage of medicines for HIV, renal 52 53 29 replacement therapy, and mental health conditions).34–36 In the future, it will be important for 54 55 30 Thailand and other countries to assess equity in access to and quality of use of medicines, 56 57 58 59 60 14 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 58 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 1 availability of medicines in health centers and hospitals, out-of-pocket and system expenditures 4 5 2 and affordability, and health outcomes as they pursue policies to achieve universal coverage. 6 7 3 8 9 4 10 11 5 12 6 13 14 7 15 For peer review only 16 8 17 18 9 19 10 20 21 11 22 23 12 24 25 13 26 27 14 28 15 29 30 16 31 32 17 33 18 34 http://bmjopen.bmj.com/ 35 19 36 37 20 38 39 21 40 41 22 42 23 on September 26, 2021 by guest. Protected copyright. 43 44 24 45 46 25 47 48 26 49 50 27 51 28 52 53 29 54 55 30 56 57 31 58 59 60 15 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 58 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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1 2 3 1 24 United States. Food and Drug Agency.Recall of Interferon alfa-2b, (Recombinant), 4 5 2 Powder for Injection, Intron A - (Schering Corporation) [Internet]. 2001 Oct 22 [cited 13 6 3 Oct 2011]. Available from: 7 4 http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandAp 8 5 proved/ApprovalApplications/TherapeuticBiologicApplications/ucm113617.htm 9 6 10 11 7 12 8 25 Damrongplasit K, Melnick GA. Early results from Thailand's 30 Baht Health Reform: 13 9 something to smile about. Health Aff (Millwood). 2009;28(3):w457-466. 14 10 15 11 26 YiengprugsawanFor V, peerCarmichael G, reviewLim L, Seubsman S, onlySleigh A. Explanation of 16 12 inequality in utilization of ambulatory care before and after universal health insurance in 17 18 13 Thailand. Health Policy Plan. 2011; 26(2): 105-14. 19 14 20 15 27 Ten Kate D. Safe at any costs? Asia Sentinel (Hong Kong) [Internet]. 2001 Jan 4 [cited 21 16 2012 Feb 6]. Available from: 22 17 http://www.asiasentinel.com/index.php?option=com_content&task=view&id=351&Itemi 23 24 18 d=392 25 19 26 20 28 Ratanawijitrasin S. Pharmaceutical policy in Thailand: a review of three decades of 27 21 government interventions. In: Eggleston K, editor. Prescribing cultures and 28 22 pharmaceutical policy in the Asia Pacific. Stanford: The Walter H. Shorenstein Asia- 29 30 23 Pacific Research Center Books; 2009. p. 79–106. 31 24 32 25 29 Tangcharoensathien V, Jongudomsuk P. From policy to implementation: Historical 33 26 events during 2001-2011 of universal coverage in Thailand. Bangkok, Thailand:

34 27 National Health Security Office; 2012. http://bmjopen.bmj.com/ 35 28 36 37 29 30 Aekplakorn W, Abbott-Klafter J, Premgamone A, et al. Prevalence and management of 38 30 diabetes and associated risk factors by regions of Thailand: Third National Health 39 31 Examination Survey 2004. Diabetes Care. 2007;30:2007–2012 40 32 41 33 31 Aekplakorn W, Abbott-Klafter J, Khonputsa P, Tatsanavivat P, Chongsuvivatwong V, 42 on September 26, 2021 by guest. Protected copyright. 43 34 Chariyalertsak S, et al. Prevalence and management of prehypertension and hypertension 44 35 by geographic regions of Thailand: the Third National Health Examination Survey, 2004. 45 36 J Hypertens. 2008; 26:191–198. 46 37 47 38 32 IMS Health. IMS Thailand Market Prognosis. 2012. 48 49 39 50 40 33 IMS Health. Pharma Pricing and Reimbursement. 2011 Mar; 16(3). 51 41 52 42 34 Khanna R. Universal Health Coverage in Thailand: What Lessons Can India Learn? 53 43 [Internet]. 2010 Dec 16 [cited 2012 Feb 7]. Available from: 54 44 http://www.mfcindia.org/main/bgpapers/bgpapers2011/am/bgpap2011r.pdf 55 56 57 58 59 60 18 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 58 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 1 35 Treerutkuarkul A. Thailand: health care for all, at a price. BullWorld Health Organ. 4 5 2 2010; 88(2): 84-5. 6 3 7 4 36 Pitayarangsarit S. The Introduction of the Universal Coverage of Health Care Policy in 8 5 Thailand: Policy Responses [PhD thesis]. London, UK: London School of Hygiene and 9 6 Tropical Medicine; 2004 [cited 2012 Feb 7]. Available from: 10 11 7 http://www.nhso.go.th/eng/download/The%20Introduction%20of%20the%20Universal% 12 8 20Coverage%20of%20Health%20Care%20Policy%20in%20Thailand_%20Policy%20Re 13 9 sponses.pdf 14 10 15 11 For peer review only 16 12 17 18 13 19 14 20 15 21 16 22 17 23 24 18 25 19 26 20 27 21 28 22 29 23 30 31 24 32 25 33 26

34 27 http://bmjopen.bmj.com/ 35 28 36 37 29 38 30 39 31 40 32 41 33 42 34 on September 26, 2021 by guest. Protected copyright. 43 44 35 45 36 46 37 47 38 48 39 49 50 40 51 41 52 42 53 43 54 44 55 56 45 57 46 58 59 60 19 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 20 of 58 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 TABLES1 4 5 2 6 Table3 1. Summary of the Impact of the Universal Coverage Scheme on Volume in the Hospital 7 Sector4 (from segmented regression results) * 8 Therapeutic Area Pre-policy trend Immediate change after Post-policy trend change 9 policy 10

11 12 DIABETES 13 Antidiabetics** 14 Insulins** 15 For peer review only 16 17 CARDIOVASCULAR DISEASE 18 19 Antihypertensives 20 Lipid Regulating Agents** 21 Cardiac Therapy 22 23 24 CANCER 25 Antineoplastics 26 27 Cytostatic Hormones 28 Immunostimulating Agents** 29 30 *Arrows5 signify a statistically significant coefficient (p<0.05) from segmented regression with linear post-policy trend term, unless noted otherwise. **Quadratic6 model (which has a squared post-policy trend term) fits better than linear model. 31 Note:7 See online appendix Table 2 and Figures 1-8 for regression coefficients and figures for all therapeutic areas. 32 8 33 9

34 http://bmjopen.bmj.com/ 35 Table10 2. Relative Impact of UCS on Sales of Medicines by Class (one and five years post policy)* 36 Therapeutic Class One Year Impact (in standard units) Five Year Impact (in standard units) 37 Predicted Observed Relative Change Predicted Observed Relative Change 38 (95% CI) (95% CI) 39 Antidiabetics 2602·91 2769·79 6·4% (-6·9, 19·7) 3669·13 5090·62 38·7% (13·5, 64·0) 40 41 Insulins 3·30 4·45 34·8% (15·1, 54·5) 4·58 12·56 174·4% (113·9, 235·0) 42 Cardiac Therapy Agents 607·27 -13·2% (-26·9, 0·6) 908·12 825·49 -9·1% (-31·9, 13·1) 699·28 on September 26, 2021 by guest. Protected copyright. 43 Lipid Regulating Agents 522·34 504·58 -3·4% (-19·9, 13·1) 781·97 1629·11 108·3% (59·8, 156·9) 44 45 Antihypertensives 3521·47 3418·79 -2·9% (-15·5, 9·7) 5200·86 6177·49 18·8% (-2·8, 40·3)** 46 Antineoplastics 35·38 34·21 -3·3% (-15·4, 8·7) 46·14 48·13 4·3% (-16·3, 24·9) 47 48 Cytostatic Hormones 29·48 30·58 3·7% (-10·1, 17·6) 39·82 47·52 19·3% (-5·1, 43·8) 49 Immunostimulating 0·65 0·43 -35·0% (-45·1, -25·0) 0·81 0·60 -26·3% (-45·0, -7·6) 50 Agents 51 *Bold11 signifies that the change is statistically significant (i.e., confidence interval does not include the null value of 0). 52 **12 The absolute five-year difference, which is estimated using more precise method, is significant. See online appendix Table 3. 53 13 54 14 55 15 56 16 57 58 17 59 60 20 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 21 of 58 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 1 Table 3. Immediate Impact of UCS on Hospital Sector Market Share* 4 5 Therapeutic Area Licensing Status Immediate post-policy 6 absolute change 7 in % market share (95% CI) 8 DIABETES 9 Antidiabetics Originator brand -0·3% (-1·6, 1·0) 10 Branded generic -12·3% (-16·0, -8·7) 11 Generic -3·5% (-5·8, -1·1) 12 13 GPO 16·1% (12·0, 20·2) 14 Insulins*** Originator brand** -0·04% (-0·4, 0·3) 15 For Branded peer generic review7·0% (2·9, 11only·1) 16 Generic -6·2% (-10·3, -2·1) 17 18 CARDIOVASCULAR DISEASE 19 20 Antihypertensives Originator brand** -0·1% (-2·3, 2·0) 21 Branded generic** -0·2% (-6·1, 1·8) 22 Generic -5·7% (-8·3, -3·0) 23 GPO 5·3% (-0·1, 10·6) 24 25 Lipid Regulating Originator brand** -7·8% (-10·2, -5·4) 26 Agents 27 Branded generic** 7·6% (5·1, 10·0) 28 Generic 0·2% (-0·4, 0·7) 29 GPO 0·2% (-0·3, 0·8) 30 Cardiac Therapy Originator brand 0·1% (-0·8, 1·0) 31 32 Branded generic** -13·5% (-20·5, -6·5) 33 Generic -4·3% (-6·2, -2·4)

34 GPO 21·6% (15·0, 28·1) http://bmjopen.bmj.com/ 35 CANCER*** 36 37 Antineoplastics Originator brand 1·1% (-1·0, 3·2) 38 Branded generic -1·0% (-5·4, 3·4) 39 Generic 0·4% (-2·7, 3·4) 40 Cytostatic Hormones Originator brand** 0·4% (-5·4, 6·1) 41 42 Branded generic** -7·7% (-12·0, -3·5) on September 26, 2021 by guest. Protected copyright. 43 Generic** 6·0% (1·4, 10·6) 44 Immunostimulating Originator brand -6·4% (-9·7, -3·0) 45 Agents 46 Branded generic 4·5% (1·7, 7·3) 47 Generic -0·2% (-0·3, 0·02) 48 49 2 *Bold signifies a statistically significant regression coefficient (p<0.05). Changes are in absolute terms (i.e., percentage point change). 3 **Quadratic model (which has a squared post-policy term) fits better than linear model. 50 4 ***GPO did not produce any insulins or cancer medicines during the study period. 51 5 Note 1: See online appendix Table 4 and Figures 9-16 for market share regression coefficients and figures for all therapeutic areas 52 6 Note 2: Aside from the immediate level changes following the policy, there were few major changes in market share. See online appendix, Table 53 7 5 for absolute one- and five-year differences. 54 8 55 9 56 10 57 11 58 59 60 21 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 22 of 58 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

1 2 3 1 Figure Index (attached in separate document):* 4 5 2 Figure 1. Standard Units Per Capita by Quarter: Insulin (Hospital vs. Retail) 6 3 7 4 Figure 2. Standard Units Per Capita by Quarter: Antihypertensives (Hospital vs. Retail) 8 5 9 6 Figure 3. Licensing Status Market Share by Quarter: Antidiabetics (Hospital Sector) 10 11 7 12 8 Figure 4. Licensing Status Market Share by Quarter: Cardiac Therapy Products (Hospital 13 9 Sector) 14 10 15 11 *The grey box inFor each figure peer represents the review 3-quarter UCS roll-out only period. 16 12 17 18 13 Online appendix (attached in separate document) 19 14 20 15 21 22 23 24 25 26 27 28 29 30 31 32 33

34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on September 26, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 22 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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Appendix Table 1. List of Medicines by ATC 1 2 Therapeutic Area Classification for Analysis Molecule Name ATC2 Classification ATC4 Classification 3 DIABETES 4 Antidiabetics ACARBOSE A10 (DRUGS USED IN DIABETES) A10L0 (A-GLUCOSIDASE INH A-DIAB) 5 Antidiabetics BUFORMIN A10 (DRUGS USED IN DIABETES) A10J1 (BIGUANIDE A-DIABS PLAIN) 6 Antidiabetics CHLORPROPAMIDE A10 (DRUGS USED IN DIABETES) A10H0 (SULPHONYLUREA A-DIABS) 7 Antidiabetics EXENATIDE A10 (DRUGS USED IN DIABETES) A10S0 (GLP-1 AGONIST A-DIABS) Antidiabetics GLIBENCLAMIDE A10 (DRUGS USED IN DIABETES) A10H0 (SULPHONYLUREA A-DIABS ) 8 Antidiabetics GLIBENCLAMIDE#METFORMIN A10 (DRUGS USED IN DIABETES) A10J2 (BIGUANIDE & S-UREA COMBS) 9 Antidiabetics GLICLAZIDE A10 (DRUGS USED IN DIABETES) A10H0 (SULPHONYLUREA A-DIABS) 10 Antidiabetics GLICLAZIDE#METFORMIN A10 (DRUGS USED IN DIABETES) A10J2 (BIGUANIDE & S-UREA COMBS) 11 Antidiabetics ForGLIMEPIRIDE peer reviewA10 (DRUGS USED onlyIN DIABETES) A10H0 (SULPHONYLUREA A-DIABS) 12 Antidiabetics GLIMEPIRIDE#METFORMIN A10 (DRUGS USED IN DIABETES) A10J2 (BIGUANIDE & S-UREA COMBS) 13 Antidiabetics GLIMEPIRIDE#ROSIGLITAZONE A10 (DRUGS USED IN DIABETES) A10K2 (GLITAZONE & S-UREA COMBS) 14 Antidiabetics GLIPIZIDE A10 (DRUGS USED IN DIABETES) A10H0 (SULPHONYLUREA A-DIABS) 15 Antidiabetics GLIQUIDONE A10 (DRUGS USED IN DIABETES) A10H0 (SULPHONYLUREA A-DIABS) Antidiabetics METFORMIN A10 (DRUGS USED IN DIABETES) A10J1 (BIGUANIDE A-DIABS PLAIN) 16 Antidiabetics METFORMIN#PIOGLITAZONE A10 (DRUGS USED IN DIABETES) A10K3 (GLITAZONE & BIGUAN COMBS)

17 Antidiabetics METFORMIN#ROSIGLITAZONE A10 (DRUGS USED IN DIABETES) A10K3http://bmjopen.bmj.com/ (GLITAZONE & BIGUAN COMBS) 18 Antidiabetics METFORMIN#SITAGLIPTIN A10 (DRUGS USED IN DIABETES) A10N3 (DPP-IV INH & BIGUAN COMB) 19 Antidiabetics METFORMIN#VILDAGLIPTIN A10 (DRUGS USED IN DIABETES) A10N3 (DPP-IV INH & BIGUAN COMB) 20 Antidiabetics PIOGLITAZONE A10 (DRUGS USED IN DIABETES) A10K1 (GLITAZONE A-DIABS PLAIN) 21 Antidiabetics REPAGLINIDE A10 (DRUGS USED IN DIABETES) A10M1 (GLINIDE A-DIABS PLAIN) 22 Antidiabetics ROSIGLITAZONE A10 (DRUGS USED IN DIABETES) A10K1 (GLITAZONE A-DIABS PLAIN) 23 Antidiabetics SITAGLIPTIN A10 (DRUGS USED IN DIABETES) A10N1 (DPP-IV INH A-DIAB PLAIN) 24 Antidiabetics VILDAGLIPTIN A10 (DRUGS USED IN DIABETES) A10N1 (DPP-IV INH A-DIAB PLAIN) Antidiabetics VOGLIBOSE A10 (DRUGS USED IN DIABETES) A10L0 (A-GLUCOSIDASE INH A-DIAB) 25

Insulins INSULIN ASPART A10 (DRUGS USED IN DIABETES) A10C1 on September 26, 2021 by guest. Protected copyright. (H INSUL+ANG FAST ACT) 26 Insulins INSULIN ASPART#INSULIN ASPART PROTAMINE CRYSTALLINE A10 (DRUGS USED IN DIABETES) A10C3 (H INSUL+ANG INT+FAST ACT) 27 Insulins INSULIN DETEMIR A10 (DRUGS USED IN DIABETES) A10C5 (H INSUL+ANG LONG ACT) 28 Insulins INSULIN GLARGINE A10 (DRUGS USED IN DIABETES) A10C5 (H INSUL+ANG LONG ACT) 29 Insulins INSULIN HUMAN BASE A10 (DRUGS USED IN DIABETES) A10C1 (H INSUL+ANG FAST ACT) 30 Insulins INSULIN HUMAN BASE#INSULIN HUMAN ISOPHANE A10 (DRUGS USED IN DIABETES) A10C3 (H INSUL+ANG INT+FAST ACT) 31 Insulins INSULIN HUMAN ISOPHANE A10 (DRUGS USED IN DIABETES) A10C2 (H INSUL+ANG INTERMED ACT) 32 Insulins INSULIN HUMAN ZINC SUSPENSION (COMPOUND) A10 (DRUGS USED IN DIABETES) A10C4 (H INSUL+ANG INT+LONG ACT) Insulins INSULIN HUMAN ZINC SUSPENSION (CRYSTALLINE) A10 (DRUGS USED IN DIABETES) A10C5 (H INSUL+ANG LONG ACT) 33 Insulins INSULIN LISPRO A10 (DRUGS USED IN DIABETES) A10C1 (H INSUL+ANG FAST ACT) 34 Insulins INSULIN LISPRO#INSULIN LISPRO PROTAMINE A10 (DRUGS USED IN DIABETES) A10C1 (H INSUL+ANG FAST ACT ) 35 Insulins INSULIN PORCINE BASE A10 (DRUGS USED IN DIABETES) A10D0 (ANIMAL INSULINS) 36 Insulins INSULIN PORCINE ISOPHANE A10 (DRUGS USED IN DIABETES) A10D0 (ANIMAL INSULINS) 37 Insulins INSULIN PORCINE ZINC SUSPENSION (COMPOUND) A10 (DRUGS USED IN DIABETES) A10D0 (ANIMAL INSULINS ) 38 39 CARIOVASCULAR DISEASE 40 Antihypertensives AJMALICINE#BUTIZIDE#RESCINNAMINE#RESERPINE C2 (ANTIHYPERTENSIVES) C2D0 (RAUWOLF ALK+OTH COM+DIUR) 41 Antihypertensives BUNAZOSIN C2 (ANTIHYPERTENSIVES) C2A2 (ANTIHYPER.PL MAINLY PERI) Antihypertensives CLONIDINE C2 (ANTIHYPERTENSIVES) C2A1 (ANTIHYPER.PL MAINLY CENT) 42 Antihypertensives CLOPAMIDE#DIHYDROERGOCRISTINE#RESERPINE C2 (ANTIHYPERTENSIVES) C2D0 (RAUWOLF ALK+OTH COM+DIUR) 43 Antihypertensives CLOPAMIDE#RESERPINE C2 (ANTIHYPERTENSIVES) C2D0 (RAUWOLF ALK+OTH COM+DIUR) 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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Antihypertensives DIHYDRALAZINE C2 (ANTIHYPERTENSIVES) C2A2 (ANTIHYPER.PL MAINLY PERI) 1 Antihypertensives DOXAZOSIN C2 (ANTIHYPERTENSIVES) C2A2 (ANTIHYPER.PL MAINLY PERI) 2 Antihypertensives HYDRALAZINE C2 (ANTIHYPERTENSIVES) C2A2 (ANTIHYPER.PL MAINLY PERI) 3 Antihypertensives HYDRALAZINE#HYDROCHLOROTHIAZIDE#RESERPINE C2 (ANTIHYPERTENSIVES) C2B2 (A-HYPERT(N V)MAINLY PERI) 4 Antihypertensives KETANSERIN C2 (ANTIHYPERTENSIVES) C2A2 (ANTIHYPER.PL MAINLY PERI) 5 Antihypertensives METHYLDOPA C2 (ANTIHYPERTENSIVES) C2A1 (ANTIHYPER.PL MAINLY CENT) 6 Antihypertensives MINOXIDIL C2 (ANTIHYPERTENSIVES) C2A2 (ANTIHYPER.PL MAINLY PERI) Antihypertensives NITROPRUSSIDE C2 (ANTIHYPERTENSIVES) C2A2 (ANTIHYPER.PL MAINLY PERI) 7 Antihypertensives PRAZOSIN C2 (ANTIHYPERTENSIVES) C2A2 (ANTIHYPER.PL MAINLY PERI) 8 Antihypertensives RESERPINE C2 (ANTIHYPERTENSIVES) C2C0 (RAUWLF ALK+OTH A-HY HERB) 9 Antihypertensives RILMENIDINE C2 (ANTIHYPERTENSIVES) C2A1 (ANTIHYPER.PL MAINLY CENT) 10 Antihypertensives 1-PROPANOL C7 (BETA BLOCKING AGENTS) C7A0 (B-BLOCKING AGENTS,PLAIN) 11 Antihypertensives ForAMILORIDE#HYDROCHLOROTHIAZIDE#TIMOLOL peer reviewC7 (BETA BLOCKING only AGENTS) C7B1 (B-BLOCK COMB HYPOT/DIURT) 12 Antihypertensives ATENOLOL C7 (BETA BLOCKING AGENTS) C7A0 (B-BLOCKING AGENTS,PLAIN) 13 Antihypertensives ATENOLOL#CHLORTALIDONE C7 (BETA BLOCKING AGENTS) C7B1 (B-BLOCK COMB HYPOT/DIURT) 14 Antihypertensives BETAXOLOL C7 (BETA BLOCKING AGENTS) C7A0 (B-BLOCKING AGENTS,PLAIN) Antihypertensives BISOPROLOL C7 (BETA BLOCKING AGENTS) C7A0 (B-BLOCKING AGENTS,PLAIN) 15 Antihypertensives BISOPROLOL#HYDROCHLOROTHIAZIDE C7 (BETA BLOCKING AGENTS) C7B1 (B-BLOCK COMB HYPOT/DIURT) 16 Antihypertensives CARVEDILOL C7 (BETA BLOCKING AGENTS) C7A0 (B-BLOCKING AGENTS,PLAIN)

17 Antihypertensives CLOPAMIDE#PINDOLOL C7 (BETA BLOCKING AGENTS) C7B1http://bmjopen.bmj.com/ (B-BLOCK COMB HYPOT/DIURT) 18 Antihypertensives LABETALOL C7 (BETA BLOCKING AGENTS) C7A0 (B-BLOCKING AGENTS,PLAIN) 19 Antihypertensives METOPROLOL C7 (BETA BLOCKING AGENTS) C7A0 (B-BLOCKING AGENTS,PLAIN) 20 Antihypertensives NEBIVOLOL C7 (BETA BLOCKING AGENTS) C7A0 (B-BLOCKING AGENTS,PLAIN ) 21 Antihypertensives OXPRENOLOL C7 (BETA BLOCKING AGENTS) C7A0 (B-BLOCKING AGENTS,PLAIN ) 22 Antihypertensives PINDOLOL C7 (BETA BLOCKING AGENTS) C7A0 (B-BLOCKING AGENTS,PLAIN ) 23 Antihypertensives PROPRANOLOL C7 (BETA BLOCKING AGENTS) C7A0 (B-BLOCKING AGENTS,PLAIN ) Antihypertensives SOTALOL C7 (BETA BLOCKING AGENTS C7A0 ) (B-BLOCKING AGENTS,PLAIN ) 24 Antihypertensives AMLODIPINE C8 (CALCIUM ANTAGONISTS) C8A0 (CALCIUM ANTAGONIST PLAIN) 25 Antihypertensives ATENOLOL#NIFEDIPINE C8 (CALCIUM ANTAGONISTS) C8B2 (CALC ANTAG/B BLOCKR COMB) on September 26, 2021 by guest. Protected copyright. 26 Antihypertensives BARNIDIPINE C8 (CALCIUM ANTAGONISTS) C8A0 (CALCIUM ANTAGONIST PLAIN) 27 Antihypertensives DILTIAZEM C8 (CALCIUM ANTAGONISTS) C8A0 (CALCIUM ANTAGONIST PLAIN) 28 Antihypertensives FELODIPINE C8 (CALCIUM ANTAGONISTS) C8A0 (CALCIUM ANTAGONIST PLAIN) 29 Antihypertensives GALLOPAMIL C8 (CALCIUM ANTAGONISTS) C8A0 (CALCIUM ANTAGONIST PLAIN) 30 Antihypertensives ISRADIPINE C8 (CALCIUM ANTAGONISTS) C8A0 (CALCIUM ANTAGONIST PLAIN) 31 Antihypertensives LACIDIPINE C8 (CALCIUM ANTAGONISTS) C8A0 (CALCIUM ANTAGONIST PLAIN) 32 Antihypertensives LERCANIDIPINE C8 (CALCIUM ANTAGONISTS) C8A0 (CALCIUM ANTAGONIST PLAIN) Antihypertensives MANIDIPINE C8 (CALCIUM ANTAGONISTS) C8A0 (CALCIUM ANTAGONIST PLAIN) 33 Antihypertensives MIBEFRADIL C8 (CALCIUM ANTAGONISTS) C8A0 (CALCIUM ANTAGONIST PLAIN) 34 Antihypertensives NICARDIPINE C8 (CALCIUM ANTAGONISTS) C8A0 (CALCIUM ANTAGONIST PLAIN) 35 Antihypertensives NIFEDIPINE C8 (CALCIUM ANTAGONISTS) C8A0 (CALCIUM ANTAGONIST PLAIN) 36 Antihypertensives NISOLDIPINE C8 (CALCIUM ANTAGONISTS) C8A0 (CALCIUM ANTAGONIST PLAIN) 37 Antihypertensives NITRENDIPINE C8 (CALCIUM ANTAGONISTS) C8A0 (CALCIUM ANTAGONIST PLAIN) 38 Antihypertensives VERAPAMIL C8 (CALCIUM ANTAGONISTS) C8A0 (CALCIUM ANTAGONIST PLAIN) 39 Antihypertensives AMILORIDE C3 (DIURETICS) C3A1 (POT SPARING AGENTS PLAIN) 40 Antihypertensives AMILORIDE#HYDROCHLOROTHIAZIDE C3 (DIURETICS) C3A5 (POT SPARING+THIAZ COMBS ) Antihypertensives BAROSMA BETULINA#CAPSICUM#METHYLENE BLUE#URGINEA SCILLAC3 (DIURETICS) C3A6 (OTHER DIURETICS) 41 Antihypertensives BAROSMA BETULINA#HYOSCYAMUS ALBUS#POTASSIUM C3 (DIURETICS) C3A6 (OTHER DIURETICS) 42 Antihypertensives BENDROFLUMETHIAZIDE#POTASSIUM C3 (DIURETICS) C3A3 (THIAZIDE+ANALOGUE PLAIN) 43 Antihypertensives BUMETANIDE C3 (DIURETICS) C3A2 (LOOP DIURETICS PLAIN) 44 Antihypertensives FUROSEMIDE C3 (DIURETICS) C3A2 (LOOP DIURETICS PLAIN) 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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Antihypertensives HYDROCHLOROTHIAZIDE C3 (DIURETICS) C3A3 (THIAZIDE+ANALOGUE PLAIN) 1 Antihypertensives HYDROCHLOROTHIAZIDE#TRIAMTERENE C3 (DIURETICS) C3A5 (POT SPARING+THIAZ COMBS) 2 Antihypertensives INDAPAMIDE C3 (DIURETICS) C3A3 (THIAZIDE+ANALOGUE PLAIN) 3 Antihypertensives SPIRONOLACTONE C3 (DIURETICS) C3A1 (POT SPARING AGENTS PLAIN) 4 Antihypertensives TORASEMIDE C3 (DIURETICS) C3A2 (LOOP DIURETICS PLAIN) 5 Antihypertensives TRIPAMIDE C3 (DIURETICS) C3A3 (THIAZIDE+ANALOGUE PLAIN) 6 Antihypertensives XIPAMIDE C3 (DIURETICS) C3A3 (THIAZIDE+ANALOGUE PLAIN) Antihypertensives ALISKIREN C9 (RENIN-ANGIOTEN SYS AGENT) C9X0 (OTH RENIN-ANGIOTEN AGENT) 7 Antihypertensives ALISKIREN#HYDROCHLOROTHIAZIDE C9 (RENIN-ANGIOTEN SYS AGENT) C9X0 (OTH RENIN-ANGIOTEN AGENT) 8 Antihypertensives AMLODIPINE#VALSARTAN C9 (RENIN-ANGIOTEN SYS AGENT) C9D3 (AT2 ANTG COMB CALC ANTAG) 9 Antihypertensives CANDESARTAN CILEXETIL C9 (RENIN-ANGIOTEN SYS AGENT) C9C0 (ANGIOTEN-II ANTAG, PLAIN) 10 Antihypertensives CANDESARTAN CILEXETIL#HYDROCHLOROTHIAZIDE C9 (RENIN-ANGIOTEN SYS AGENT) C9D1 (AT2 ANTG COMB C2 &/O DIU) 11 Antihypertensives ForCAPTOPRIL peer reviewC9 (RENIN-ANGIOTEN only SYS AGENT) C9A0 (ACE INHIBITORS PLAIN) 12 Antihypertensives CILAZAPRIL C9 (RENIN-ANGIOTEN SYS AGENT) C9A0 (ACE INHIBITORS PLAIN) 13 Antihypertensives DELAPRIL C9 (RENIN-ANGIOTEN SYS AGENT) C9A0 (ACE INHIBITORS PLAIN) 14 Antihypertensives ENALAPRIL C9 (RENIN-ANGIOTEN SYS AGENT) C9A0 (ACE INHIBITORS PLAIN) Antihypertensives EPROSARTAN C9 (RENIN-ANGIOTEN SYS AGENT) C9C0 (ANGIOTEN-II ANTAG, PLAIN) 15 Antihypertensives FOSINOPRIL C9 (RENIN-ANGIOTEN SYS AGENT) C9A0 (ACE INHIBITORS PLAIN) 16 Antihypertensives FOSINOPRIL#HYDROCHLOROTHIAZIDE C9 (RENIN-ANGIOTEN SYS AGENT) C9B1 (ACE INH COMB+A-HYP/DIUR)

17 Antihypertensives HYDROCHLOROTHIAZIDE#IRBESARTAN C9 (RENIN-ANGIOTEN SYS AGENT) C9D1http://bmjopen.bmj.com/ (AT2 ANTG COMB C2 &/O DIU) 18 Antihypertensives HYDROCHLOROTHIAZIDE#LOSARTAN C9 (RENIN-ANGIOTEN SYS AGENT) C9D1 (AT2 ANTG COMB C2 &/O DIU) 19 Antihypertensives HYDROCHLOROTHIAZIDE#OLMESARTAN MEDOXOMIL C9 (RENIN-ANGIOTEN SYS AGENT) C9D1 (AT2 ANTG COMB C2 &/O DIU) 20 Antihypertensives HYDROCHLOROTHIAZIDE#QUINAPRIL C9 (RENIN-ANGIOTEN SYS AGENT) C9B1 (ACE INH COMB+A-HYP/DIUR) 21 Antihypertensives HYDROCHLOROTHIAZIDE#RAMIPRIL C9 (RENIN-ANGIOTEN SYS AGENT) C9B1 (ACE INH COMB+A-HYP/DIUR) 22 Antihypertensives HYDROCHLOROTHIAZIDE#TELMISARTAN C9 (RENIN-ANGIOTEN SYS AGENT) C9D1 (AT2 ANTG COMB C2 &/O DIU) 23 Antihypertensives HYDROCHLOROTHIAZIDE#VALSARTAN C9 (RENIN-ANGIOTEN SYS AGENT) C9D1 (AT2 ANTG COMB C2 &/O DIU) Antihypertensives IMIDAPRIL C9 (RENIN-ANGIOTEN SYS AGENT) C9A0 (ACE INHIBITORS PLAIN) 24 Antihypertensives INDAPAMIDE#PERINDOPRIL C9 (RENIN-ANGIOTEN SYS AGENT) C9B1 (ACE INH COMB+A-HYP/DIUR) 25 Antihypertensives IRBESARTAN C9 (RENIN-ANGIOTEN SYS AGENT) C9C0 (ANGIOTEN-II ANTAG, PLAIN) on September 26, 2021 by guest. Protected copyright. 26 Antihypertensives LISINOPRIL C9 (RENIN-ANGIOTEN SYS AGENT) C9A0 (ACE INHIBITORS PLAIN ) 27 Antihypertensives LOSARTAN C9 (RENIN-ANGIOTEN SYS AGENT) C9C0 (ANGIOTEN-II ANTAG, PLAIN) 28 Antihypertensives OLMESARTAN MEDOXOMIL C9 (RENIN-ANGIOTEN SYS AGENT) C9C0 (ANGIOTEN-II ANTAG, PLAIN) 29 Antihypertensives PERINDOPRIL C9 (RENIN-ANGIOTEN SYS AGENT) C9A0 (ACE INHIBITORS PLAIN ) 30 Antihypertensives QUINAPRIL C9 (RENIN-ANGIOTEN SYS AGENT) C9A0 (ACE INHIBITORS PLAIN ) 31 Antihypertensives RAMIPRIL C9 (RENIN-ANGIOTEN SYS AGENT) C9A0 (ACE INHIBITORS PLAIN) 32 Antihypertensives TELMISARTAN C9 (RENIN-ANGIOTEN SYS AGENT) C9C0 (ANGIOTEN-II ANTAG, PLAIN) Antihypertensives VALSARTAN C9 (RENIN-ANGIOTEN SYS AGENT) C9C0 (ANGIOTEN-II ANTAG, PLAIN) 33 Cardiac Therapy ADENOSINE C1 (CARDIAC THERAPY) C1B0 (ANTIARRHYTHMICS) 34 Cardiac Therapy AMIODARONE C1 (CARDIAC THERAPY) C1B0 (ANTIARRHYTHMICS) 35 Cardiac Therapy AMRINONE C1 (CARDIAC THERAPY) C1F0 (POSITIVE INOTROPIC AGENT) 36 Cardiac Therapy CAFFEINE#ETAMIVAN C1 (CARDIAC THERAPY) C1C1 (CARDIAC STM EX DOPAM AGT) 37 Cardiac Therapy DIGITALIS PURPUREA C1 (CARDIAC THERAPY) C1A1 (CARDIAC GLYCOSIDES PLAIN) 38 Cardiac Therapy DIGITOXIN C1 (CARDIAC THERAPY) C1A1 (CARDIAC GLYCOSIDES PLAIN) 39 Cardiac Therapy DIGOXIN C1 (CARDIAC THERAPY) C1A1 (CARDIAC GLYCOSIDES PLAIN) 40 Cardiac Therapy DISOPYRAMIDE C1 (CARDIAC THERAPY) C1B0 (ANTIARRHYTHMICS) Cardiac Therapy DOBUTAMINE C1 (CARDIAC THERAPY) C1C2 (CARDIAC DOPAMINERG AGENT) 41 Cardiac Therapy DOPAMINE C1 (CARDIAC THERAPY) C1C2 (CARDIAC DOPAMINERG AGENT) 42 Cardiac Therapy EPINEPHRINE C1 (CARDIAC THERAPY) C1C1 (CARDIAC STM EX DOPAM AGT) 43 Cardiac Therapy ETAFEDRINE C1 (CARDIAC THERAPY) C1C1 (CARDIAC STM EX DOPAM AGT) 44 Cardiac Therapy ETILEFRINE C1 (CARDIAC THERAPY) C1C1 (CARDIAC STM EX DOPAM AGT) 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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Cardiac Therapy FLECAINIDE C1 (CARDIAC THERAPY) C1B0 (ANTIARRHYTHMICS) 1 Cardiac Therapy GLYCINE MAX#UBIDECARENONE C1 (CARDIAC THERAPY) C1X0 (ALL OTHER CARDIAC PREPS) 2 Cardiac Therapy ISOPRENALINE C1 (CARDIAC THERAPY) C1C1 (CARDIAC STM EX DOPAM AGT) 3 Cardiac Therapy ISOSORBIDE DINITRATE C1 (CARDIAC THERAPY) C1E0 (NITRITES AND NITRATES) 4 Cardiac Therapy ISOSORBIDE MONONITRATE C1 (CARDIAC THERAPY) C1E0 (NITRITES AND NITRATES) 5 Cardiac Therapy IVABRADINE C1 (CARDIAC THERAPY) C1D0 (CORONRY THER EXC C AN+NI) 6 Cardiac Therapy LIDOCAINE C1 (CARDIAC THERAPY) C1B0 (ANTIARRHYTHMICS) Cardiac Therapy MAGNESIUM#POTASSIUM#PROCAINE C1 (CARDIAC THERAPY) C1X0 (ALL OTHER CARDIAC PREPS) 7 Cardiac Therapy METARAMINOL C1 (CARDIAC THERAPY) C1C1 (CARDIAC STM EX DOPAM AGT) 8 Cardiac Therapy METILDIGOXIN C1 (CARDIAC THERAPY) C1A1 (CARDIAC GLYCOSIDES PLAIN) 9 Cardiac Therapy MEXILETINE C1 (CARDIAC THERAPY) C1B0 (ANTIARRHYTHMICS) 10 Cardiac Therapy MIDODRINE C1 (CARDIAC THERAPY) C1C1 (CARDIAC STM EX DOPAM AGT) 11 Cardiac Therapy ForMILRINONE peer reviewC1 (CARDIAC THERAPY) only C1F0 (POSITIVE INOTROPIC AGENT) 12 Cardiac Therapy NITROGLYCERIN C1 (CARDIAC THERAPY) C1E0 (NITRITES AND NITRATES) 13 Cardiac Therapy NOREPINEPHRINE C1 (CARDIAC THERAPY) C1C1 (CARDIAC STM EX DOPAM AGT) 14 Cardiac Therapy OXYFEDRINE C1 (CARDIAC THERAPY) C1D0 (CORONRY THER EXC C AN+NI) Cardiac Therapy PENTAERYTHRITYL TETRANITRATE C1 (CARDIAC THERAPY) C1E0 (NITRITES AND NITRATES) 15 Cardiac Therapy PROCAINAMIDE C1 (CARDIAC THERAPY) C1B0 (ANTIARRHYTHMICS) 16 Cardiac Therapy PROPAFENONE C1 (CARDIAC THERAPY) C1B0 (ANTIARRHYTHMICS)

17 Cardiac Therapy QUINIDINE C1 (CARDIAC THERAPY) C1B0http://bmjopen.bmj.com/ (ANTIARRHYTHMICS) 18 Cardiac Therapy TOCAINIDE C1 (CARDIAC THERAPY) C1B0 (ANTIARRHYTHMICS) 19 Cardiac Therapy TRIMETAZIDINE C1 (CARDIAC THERAPY) C1D0 (CORONRY THER EXC C AN+NI) 20 Cardiac Therapy UBIDECARENONE C1 (CARDIAC THERAPY) C1X0 (ALL OTHER CARDIAC PREPS) 21 Cardiac Therapy UBIQUINONE(S) C1 (CARDIAC THERAPY) C1X0 (ALL OTHER CARDIAC PREPS) 22 Lipid Regulating ACIPIMOX C10 (LIP.REG./ANTI-ATH. PREPS) C10A9 (OTH.CHOLEST&TRIGLY.REGUL) 23 Lipid Regulating ALLIUM SATIVUM C10 (LIP.REG./ANTI-ATH. PREPS) C10B0 (ANTI-ATHEROMA NATRL ORIG) Lipid Regulating ALLIUM SATIVUM#ARACHIS HYPOGAEA C10 (LIP.REG./ANTI-ATH. PREPS) C10B0 (ANTI-ATHEROMA NATRL ORIG) 24 Lipid Regulating ALLIUM SATIVUM#SOYA LECITHIN C10 (LIP.REG./ANTI-ATH. PREPS) C10B0 (ANTI-ATHEROMA NATRL ORIG) 25 Lipid Regulating AMLODIPINE#ATORVASTATIN C11 (C.V. MULTITH. COMB PROD) C11A1 (LIPREG.CV.MULT-TH.FX.COM) on September 26, 2021 by guest. Protected copyright. 26 Lipid Regulating ATORVASTATIN C10 (LIP.REG./ANTI-ATH. PREPS) C10A1 (STATINS (HMG-COA RED)) 27 Lipid Regulating BEZAFIBRATE C10 (LIP.REG./ANTI-ATH. PREPS) C10A2 (FIBRATES) 28 Lipid Regulating CERIVASTATIN C10 (LIP.REG./ANTI-ATH. PREPS) C10A1 (STATINS (HMG-COA RED)) 29 Lipid Regulating COLESTYRAMINE C10 (LIP.REG./ANTI-ATH. PREPS) C10A3 (ION-EXCHANGE RESINS) 30 Lipid Regulating DOCOSAHEXANOIC ACID#EICOSAPENTAENOIC ACID C10 (LIP.REG./ANTI-ATH. PREPS) C10B0 (ANTI-ATHEROMA NATRL ORIG) 31 Lipid Regulating DOCOSAHEXANOIC ACID#EICOSAPENTAENOIC ACID#VITAMIN E C10 (LIP.REG./ANTI-ATH. PREPS) C10B0 (ANTI-ATHEROMA NATRL ORIG) 32 Lipid Regulating EZETIMIBE C10 (LIP.REG./ANTI-ATH. PREPS) C10A9 (OTH.CHOLEST&TRIGLY.REGUL) Lipid Regulating EZETIMIBE#SIMVASTATIN C10 (LIP.REG./ANTI-ATH. PREPS) C10C0 (LIP.REG.CO.W.OTH.LIP.REG) 33 Lipid Regulating FENOFIBRATE C10 (LIP.REG./ANTI-ATH. PREPS) C10A2 (FIBRATES) 34 Lipid Regulating FISH C10 (LIP.REG./ANTI-ATH. PREPS) C10B0 (ANTI-ATHEROMA NATRL ORIG) 35 Lipid Regulating FISH#SOYA LECITHIN C10 (LIP.REG./ANTI-ATH. PREPS) C10B0 (ANTI-ATHEROMA NATRL ORIG) 36 Lipid Regulating FLUVASTATIN C10 (LIP.REG./ANTI-ATH. PREPS) C10A1 (STATINS (HMG-COA RED) ) 37 Lipid Regulating GEMFIBROZIL C10 (LIP.REG./ANTI-ATH. PREPS) C10A2 (FIBRATES) 38 Lipid Regulating LECITHIN C10 (LIP.REG./ANTI-ATH. PREPS) C10B0 (ANTI-ATHEROMA NATRL ORIG) 39 Lipid Regulating LECITHIN#SOYA LECITHIN C10 (LIP.REG./ANTI-ATH. PREPS) C10B0 (ANTI-ATHEROMA NATRL ORIG) 40 Lipid Regulating NICOTINIC ACID C10 (LIP.REG./ANTI-ATH. PREPS) C10A9 (OTH.CHOLEST&TRIGLY.REGUL) Lipid Regulating PITAVASTATIN C10 (LIP.REG./ANTI-ATH. PREPS) C10A1 (STATINS (HMG-COA RED)) 41 Lipid Regulating PRAVASTATIN C10 (LIP.REG./ANTI-ATH. PREPS) C10A1 (STATINS (HMG-COA RED)) 42 Lipid Regulating PROBUCOL C10 (LIP.REG./ANTI-ATH. PREPS) C10A9 (OTH.CHOLEST&TRIGLY.REGUL) 43 Lipid Regulating PYRICARBATE C10 (LIP.REG./ANTI-ATH. PREPS) C10A9 (OTH.CHOLEST&TRIGLY.REGUL) 44 Lipid Regulating ROSUVASTATIN C10 (LIP.REG./ANTI-ATH. PREPS) C10A1 (STATINS (HMG-COA RED)) 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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Lipid Regulating SALMON C10 (LIP.REG./ANTI-ATH. PREPS) C10B0 (ANTI-ATHEROMA NATRL ORIG) 1 Lipid Regulating SIMVASTATIN C10 (LIP.REG./ANTI-ATH. PREPS) C10A1 (STATINS (HMG-COA RED)) 2 Lipid Regulating SOYA LECITHIN C10 (LIP.REG./ANTI-ATH. PREPS) C10B0 (ANTI-ATHEROMA NATRL ORIG) 3 4 CANCER 5 Antineoplastics ALEMTUZUMAB L1 (ANTINEOPLASTICS) L1X3 (ANTINEOPLASTIC MABS) 6 Antineoplastics ALTRETAMINE L1 (ANTINEOPLASTICS) L1A0 (ALKYLATING AGENTS) Antineoplastics ASPARAGINASE L1 (ANTINEOPLASTICS) L1X9 (ALL OTH. ANTINEOPLASTICS) 7 Antineoplastics AZACITIDINE L1 (ANTINEOPLASTICS) L1B0 (ANTIMETABOLITES) 8 Antineoplastics BEVACIZUMAB L1 (ANTINEOPLASTICS) L1X3 (ANTINEOPLASTIC MABS) 9 Antineoplastics BLEOMYCIN L1 (ANTINEOPLASTICS) L1D0 (ANTINEOPLAS. ANTIBIOTICS) 10 Antineoplastics BORTEZOMIB L1 (ANTINEOPLASTICS) L1X9 (ALL OTH. ANTINEOPLASTICS) 11 Antineoplastics ForBUSULFAN peer reviewL1 (ANTINEOPLASTICS) only L1A0 (ALKYLATING AGENTS) 12 Antineoplastics CAPECITABINE L1 (ANTINEOPLASTICS) L1B0 (ANTIMETABOLITES) 13 Antineoplastics CARBOPLATIN L1 (ANTINEOPLASTICS) L1X2 (PLATINUM COMPOUNDS) 14 Antineoplastics CARMUSTINE L1 (ANTINEOPLASTICS) L1A0 (ALKYLATING AGENTS) Antineoplastics CETUXIMAB L1 (ANTINEOPLASTICS) L1X3 (ANTINEOPLASTIC MABS) 15 Antineoplastics CHLORAMBUCIL L1 (ANTINEOPLASTICS) L1A0 (ALKYLATING AGENTS) 16 Antineoplastics CHLORMETHINE L1 (ANTINEOPLASTICS) L1A0 (ALKYLATING AGENTS )

17 Antineoplastics CISPLATIN L1 (ANTINEOPLASTICS) L1X2http://bmjopen.bmj.com/ (PLATINUM COMPOUNDS) 18 Antineoplastics CLADRIBINE L1 (ANTINEOPLASTICS) L1B0 (ANTIMETABOLITES) 19 Antineoplastics CYCLOPHOSPHAMIDE L1 (ANTINEOPLASTICS) L1A0 (ALKYLATING AGENTS) 20 Antineoplastics CYTARABINE L1 (ANTINEOPLASTICS) L1B0 (ANTIMETABOLITES) 21 Antineoplastics DACARBAZINE L1 (ANTINEOPLASTICS) L1A0 (ALKYLATING AGENTS) 22 Antineoplastics DACTINOMYCIN L1 (ANTINEOPLASTICS) L1D0 (ANTINEOPLAS. ANTIBIOTICS) 23 Antineoplastics DASATINIB L1 (ANTINEOPLASTICS) L1X4 (A-NEO PROTEIN KINASE INH) Antineoplastics DECITABINE L1 (ANTINEOPLASTICS) L1B0 (ANTIMETABOLITES) 24 Antineoplastics DOCETAXEL L1 (ANTINEOPLASTICS) L1C0 (VINCA ALKALOIDS ) 25 Antineoplastics DOXORUBICIN L1 (ANTINEOPLASTICS) L1D0 (ANTINEOPLAS. ANTIBIOTICS) on September 26, 2021 by guest. Protected copyright. 26 Antineoplastics EPIRUBICIN L1 (ANTINEOPLASTICS) L1D0 (ANTINEOPLAS. ANTIBIOTICS) 27 Antineoplastics ERLOTINIB L1 (ANTINEOPLASTICS) L1X4 (A-NEO PROTEIN KINASE INH) 28 Antineoplastics ETOPOSIDE L1 (ANTINEOPLASTICS) L1C0 (VINCA ALKALOIDS) 29 Antineoplastics FLUDARABINE L1 (ANTINEOPLASTICS) L1B0 (ANTIMETABOLITES) 30 Antineoplastics FLUOROURACIL L1 (ANTINEOPLASTICS) L1B0 (ANTIMETABOLITES) 31 Antineoplastics GEFITINIB L1 (ANTINEOPLASTICS) L1X4 (A-NEO PROTEIN KINASE INH) 32 Antineoplastics GEMCITABINE L1 (ANTINEOPLASTICS) L1B0 (ANTIMETABOLITES) Antineoplastics HYDROXYCARBAMIDE L1 (ANTINEOPLASTICS) L1X9 (ALL OTH. ANTINEOPLASTICS) 33 Antineoplastics IBRITUMOMAB TIUXETAN L1 (ANTINEOPLASTICS) L1X3 (ANTINEOPLASTIC MABS) 34 Antineoplastics IDARUBICIN L1 (ANTINEOPLASTICS) L1D0 (ANTINEOPLAS. ANTIBIOTICS) 35 Antineoplastics IFOSFAMIDE L1 (ANTINEOPLASTICS) L1A0 (ALKYLATING AGENTS) 36 Antineoplastics IMATINIB L1 (ANTINEOPLASTICS) L1X4 (A-NEO PROTEIN KINASE INH) 37 Antineoplastics IRINOTECAN L1 (ANTINEOPLASTICS) L1C0 (VINCA ALKALOIDS) 38 Antineoplastics IXABEPILONE L1 (ANTINEOPLASTICS) L1X9 (ALL OTH. ANTINEOPLASTICS) 39 Antineoplastics LAPATINIB L1 (ANTINEOPLASTICS) L1X4 (A-NEO PROTEIN KINASE INH) 40 Antineoplastics LOMUSTINE L1 (ANTINEOPLASTICS) L1A0 (ALKYLATING AGENTS) Antineoplastics MELPHALAN L1 (ANTINEOPLASTICS) L1A0 (ALKYLATING AGENTS) 41 Antineoplastics MERCAPTOPURINE L1 (ANTINEOPLASTICS) L1B0 (ANTIMETABOLITES) 42 Antineoplastics METHOTREXATE L1 (ANTINEOPLASTICS) L1B0 (ANTIMETABOLITES) 43 Antineoplastics MITOMYCIN L1 (ANTINEOPLASTICS) L1D0 (ANTINEOPLAS. ANTIBIOTICS) 44 Antineoplastics MITOXANTRONE L1 (ANTINEOPLASTICS) L1D0 (ANTINEOPLAS. ANTIBIOTICS) 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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Antineoplastics NILOTINIB L1 (ANTINEOPLASTICS) L1X4 (A-NEO PROTEIN KINASE INH) 1 Antineoplastics OXALIPLATIN L1 (ANTINEOPLASTICS) L1X2 (PLATINUM COMPOUNDS) 2 Antineoplastics PACLITAXEL L1 (ANTINEOPLASTICS) L1C0 (VINCA ALKALOIDS) 3 Antineoplastics PEMETREXED L1 (ANTINEOPLASTICS) L1B0 (ANTIMETABOLITES) 4 Antineoplastics PROCARBAZINE L1 (ANTINEOPLASTICS) L1X9 (ALL OTH. ANTINEOPLASTICS) 5 Antineoplastics RITUXIMAB L1 (ANTINEOPLASTICS) L1X3 (ANTINEOPLASTIC MABS) 6 Antineoplastics SORAFENIB L1 (ANTINEOPLASTICS) L1X4 (A-NEO PROTEIN KINASE INH) Antineoplastics SUNITINIB L1 (ANTINEOPLASTICS) L1X4 (A-NEO PROTEIN KINASE INH) 7 Antineoplastics TEGAFUR L1 (ANTINEOPLASTICS) L1B0 (ANTIMETABOLITES) 8 Antineoplastics TEGAFUR#URACIL L1 (ANTINEOPLASTICS) L1B0 (ANTIMETABOLITES) 9 Antineoplastics TEMOZOLOMIDE L1 (ANTINEOPLASTICS) L1A0 (ALKYLATING AGENTS) 10 Antineoplastics TIOGUANINE L1 (ANTINEOPLASTICS) L1B0 (ANTIMETABOLITES) 11 Antineoplastics ForTOPOTECAN peer reviewL1 (ANTINEOPLASTICS) only L1C0 (VINCA ALKALOIDS) 12 Antineoplastics TRASTUZUMAB L1 (ANTINEOPLASTICS) L1X3 (ANTINEOPLASTIC MABS) 13 Antineoplastics TRETINOIN L1 (ANTINEOPLASTICS) L1X9 (ALL OTH. ANTINEOPLASTICS) 14 Antineoplastics VINBLASTINE L1 (ANTINEOPLASTICS) L1C0 (VINCA ALKALOIDS) Antineoplastics VINCRISTINE L1 (ANTINEOPLASTICS) L1C0 (VINCA ALKALOIDS) 15 Antineoplastics VINORELBINE L1 (ANTINEOPLASTICS) L1C0 (VINCA ALKALOIDS) 16 Cytostatic Hormones AMINOGLUTETHIMIDE L2 (CYTOSTATIC HORMONE THER) L2B3 (CYTOSTAT AROMATASE INHIB)

17 Cytostatic Hormones ANASTROZOLE L2 (CYTOSTATIC HORMONE THER) L2B3http://bmjopen.bmj.com/ (CYTOSTAT AROMATASE INHIB) 18 Cytostatic Hormones BICALUTAMIDE L2 (CYTOSTATIC HORMONE THER) L2B2 (CYTO ANTI-ANDROGENS) 19 Cytostatic Hormones BUSERELIN L2 (CYTOSTATIC HORMONE THER) L2A3 (CYTO GONAD HORMON ANALOG) 20 Cytostatic Hormones CYPROTERONE L2 (CYTOSTATIC HORMONE THER) L2B2 (CYTO ANTI-ANDROGENS) 21 Cytostatic Hormones EXEMESTANE L2 (CYTOSTATIC HORMONE THER) L2B3 (CYTOSTAT AROMATASE INHIB) 22 Cytostatic Hormones FLUTAMIDE L2 (CYTOSTATIC HORMONE THER) L2B2 (CYTO ANTI-ANDROGENS) 23 Cytostatic Hormones FORMESTANE L2 (CYTOSTATIC HORMONE THER) L2B3 (CYTOSTAT AROMATASE INHIB) Cytostatic Hormones FULVESTRANT L2 (CYTOSTATIC HORMONE THER) L2B9 (OTH CYTO HORMON ANTAGIST) 24 Cytostatic Hormones GOSERELIN L2 (CYTOSTATIC HORMONE THER) L2A3 (CYTO GONAD HORMON ANALOG) 25 Cytostatic Hormones LETROZOLE L2 (CYTOSTATIC HORMONE THER) L2B3 (CYTOSTAT AROMATASE INHIB) on September 26, 2021 by guest. Protected copyright. 26 Cytostatic Hormones LEUPRORELIN L2 (CYTOSTATIC HORMONE THER) L2A3 (CYTO GONAD HORMON ANALOG) 27 Cytostatic Hormones MEDROXYPROGESTERONE L2 (CYTOSTATIC HORMONE THER) L2A2 (CYTOSTATIC PROGESTOGENS ) 28 Cytostatic Hormones MEGESTROL L2 (CYTOSTATIC HORMONE THER) L2A2 (CYTOSTATIC PROGESTOGENS ) 29 Cytostatic Hormones TAMOXIFEN L2 (CYTOSTATIC HORMONE THER) L2B1 (CYTO ANTI-OESTROGENS) 30 Cytostatic Hormones TOREMIFENE L2 (CYTOSTATIC HORMONE THER) L2B1 (CYTO ANTI-OESTROGENS) 31 Cytostatic Hormones TRIPTORELIN L2 (CYTOSTATIC HORMONE THER) L2A3 (CYTO GONAD HORMON ANALOG) 32 Immunostimulating Agents FILGRASTIM L3 (IMMUNOSTIMULATING AGENTS) L3A1 (COLONY-STIMULATING FACT.) Immunostimulating Agents INTERFERON ALFA L3 (IMMUNOSTIMULATING AGENTS) L3B1 (INTERFERONS ALPHA) 33 Immunostimulating Agents INTERFERON ALFA-2A L3 (IMMUNOSTIMULATING AGENTS) L3B1 (INTERFERONS ALPHA) 34 Immunostimulating Agents INTERFERON ALFA-2B L3 (IMMUNOSTIMULATING AGENTS) L3B1 (INTERFERONS ALPHA) 35 Immunostimulating Agents INTERFERON ALFA-N1 L3 (IMMUNOSTIMULATING AGENTS) L3B1 (INTERFERONS ALPHA) 36 Immunostimulating Agents INTERFERON BETA-1A L3 (IMMUNOSTIMULATING AGENTS) L3B2 (INTERFERONS BETA) 37 Immunostimulating Agents INTERFERON BETA-1B L3 (IMMUNOSTIMULATING AGENTS) L3B2 (INTERFERONS BETA) 38 Immunostimulating Agents LENOGRASTIM L3 (IMMUNOSTIMULATING AGENTS) L3A1 (COLONY-STIMULATING FACT.) 39 Immunostimulating Agents MOLGRAMOSTIM L3 (IMMUNOSTIMULATING AGENTS) L3A1 (COLONY-STIMULATING FACT.) 40 Immunostimulating Agents PEGFILGRASTIM L3 (IMMUNOSTIMULATING AGENTS) L3A1 (COLONY-STIMULATING FACT.) Immunostimulating Agents TETRACHLORODECAOXIDE L3 (IMMUNOSTIMULATING AGENTS) L3A9 (OTH.IMMUNOSTIM.EX.INTFRN) 41 Immunostimulating Agents THYMALFASIN L3 (IMMUNOSTIMULATING AGENTS) L3A9 (OTH.IMMUNOSTIM.EX.INTFRN) 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 29 of 58 BMJ Open

1 2 3 STROBE Checklist: Impact of Universal Health Coverage in Thailand on Sales and Market BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from 4 5 Share of Medicines for Non-Communicable Diseases 6 7 8 STROBE Statement—checklist of items that should be included in reports of observational studies 9 10 Item 11 No Recommendation 12 13 Title and abstract 1 (a) Indicate the study’s design with a commonly used term in the title or the abstract 14 (b) Provide in the abstract an informative and balanced summary of what was done 15 and what was found 16 17 Introduction For peer review only 18 Background/rationale 2 Explain the scientific background and rationale for the investigation being reported 19 Objectives 3 State specific objectives, including any prespecified hypotheses 20 21 Methods 22 Study design 4 Present key elements of study design early in the paper 23 24 NOTE: We use an interrupted time series design, which is a robust longitudinal 25 observational design. 26 Setting 5 Describe the setting, locations, and relevant dates, including periods of recruitment, 27 28 exposure, follow-up, and data collection 29 Participants 6  (a) Cohort study—Give the eligibility criteria, and the sources and methods of 30 selection of participants. Describe methods of follow-up 31 Case-control study—Give the eligibility criteria, and the sources and methods of 32 33 case ascertainment and control selection. Give the rationale for the choice of cases 34 and controls 35 Cross-sectional study—Give the eligibility criteria, and the sources and methods of 36 37 selection of participants 38 (b) Cohort study—For matched studies, give matching criteria and number of http://bmjopen.bmj.com/ 39 exposed and unexposed 40 Case-control study—For matched studies, give matching criteria and the number of 41 42 controls per case 43 NOTE: We explain the data source and methods of selection (i.e., hospital vs. 44 pharmacy sales data – the latter serves as a non-equivalent comparison group) 45 46 and give the rationale for the choice of therapeutic classes and date range. 47 Variables 7 Clearly define all outcomes, exposures, predictors, potential confounders, and effect on September 26, 2021 by guest. Protected copyright. 48 modifiers. Give diagnostic criteria, if applicable 49 50 Data sources/ 8* For each variable of interest, give sources of data and details of methods of 51 measurement assessment (measurement). Describe comparability of assessment methods if there is 52 more than one group 53 Bias 9 Describe any efforts to address potential sources of bias 54 55 Study size 10 Explain how the study size was arrived at 56 Quantitative variables 11 Explain how quantitative variables were handled in the analyses. If applicable, 57 describe which groupings were chosen and why 58 59 Statistical methods 12 (a) Describe all statistical methods, including those used to control for confounding 60 (b) Describe any methods used to examine subgroups and interactions (c) Explain how missing data were addressed (d) Cohort study—If applicable, explain how loss to follow-up was addressed

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1 2 Case-control study—If applicable, explain how matching of cases and controls was

3 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from addressed 4 5 Cross-sectional study—If applicable, describe analytical methods taking account of 6 sampling strategy 7 (e) Describe any sensitivity analyses 8 9 Continued on next page 10 11 12 13 14 15 16 17 For peer review only 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 http://bmjopen.bmj.com/ 39 40 41 42 43 44 45 46 47 on September 26, 2021 by guest. Protected copyright. 48 49 50 51 52 53 54 55 56 57 58 59 60

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3 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from 4 Results 5 Participants 13*NA (a) Report numbers of individuals at each stage of study—eg numbers potentially eligible, 6 examined for eligibility, confirmed eligible, included in the study, completing follow-up, 7 8 and analysed 9 (b) Give reasons for non-participation at each stage 10 (c) Consider use of a flow diagram 11 12 Descriptive 14* (a) Give characteristics of study participants (eg demographic, clinical, social) and 13 data information on exposures and potential confounders 14 (b) Indicate number of participants with missing data for each variable of interest 15 16 (c) Cohort study—Summarise follow-up time (eg, average and total amount) 17 ForNOTE: peer We give the characteristics review of the therapeutic only classes (i.e., number subclasses, 18 medicines within each subclass). 19 Outcome data 15* Cohort study—Report numbers of outcome events or summary measures over time 20 21 Case-control study—Report numbers in each exposure category, or summary measures of 22 exposure 23 Cross-sectional study—Report numbers of outcome events or summary measures 24 25 NOTE: We report numbers of outcome events over time. 26 Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their 27 precision (eg, 95% confidence interval). Make clear which confounders were adjusted for 28 29 and why they were included 30 (b) Report category boundaries when continuous variables were categorized 31 (c) If relevant, consider translating estimates of relative risk into absolute risk for a 32 meaningful time period 33 34 Other analyses 17 Report other analyses done—eg analyses of subgroups and interactions, and sensitivity 35 analyses 36 37 Discussion 38 Key results 18 Summarise key results with reference to study objectives http://bmjopen.bmj.com/ 39 Limitations 19 Discuss limitations of the study, taking into account sources of potential bias or 40 41 imprecision. Discuss both direction and magnitude of any potential bias 42 Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, 43 multiplicity of analyses, results from similar studies, and other relevant evidence 44 45 Generalisability 21 Discuss the generalisability (external validity) of the study results 46 Other information 47 on September 26, 2021 by guest. Protected copyright. Funding 22 Give the source of funding and the role of the funders for the present study and, if 48 49 applicable, for the original study on which the present article is based 50 51 *Give information separately for cases and controls in case-control studies and, if applicable, for exposed and 52 53 unexposed groups in cohort and cross-sectional studies. 54 55 Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and 56 published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely 57 58 available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at 59 http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is 60 available at www.strobe-statement.org.

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7 8 9 1 TITLE PAGE Formatted 10 2 11 3 Impact of Universal Health Insurance Coverage in Thailand on Sales and Market Share of 12 4 Medicines for Non-Communicable Diseases: an Interrupted Time Series Study 13 5 6 Laura Faden Garabedian, MPH1, Dennis Ross-Degnan, ScD1, Sauwakon Ratanawijitrasin, PhD2, 14 3 1 15 7 Peter Stephens, MA , Anita Wagner, PharmD, MPH, DrPH 8 For peer review only 16 9 Institutions: 17 10 1 Drug Policy Research Group and WHO Collaborating Center in Pharmaceutical Policy 18 11 Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care 19 12 Institute 20 13 133 Brookline Ave., Sixth Floor 21 14 Boston, MA, USA 22 15 23 16 Dennis Ross-Degnan and Anita Wagner are Associate Professors. Laura Faden Garabedian is a 24 17 Research Fellow and PhD Candidate. 25 18 26 19 Corresponding author: Laura Faden Garabedian 27 20 Phone: +1 617 509 9921 28 21 Email: [email protected] 29 22 2 30 23 Professor 31 24 Faculty of Social Sciences and Humanities, Mahidol University 25 Salaya, Buddhamonthon, Nakhonpathom, 73170 Thailand 32 33 26 27 3 Director, Public Health Affairs

34 http://bmjopen.bmj.com/ 28 IMS Health 35 29 7 Harewood Avenue 36 30 London, NW1 6JB, UK 37 31 38 32 Study Design: Observational study (interrupted time series design) 39 33 40 34 Acknowledgements: We gratefully acknowledge support of statistical analyses by Dr. Fang Formatted: Font: Bold 41 35 Zhang, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim 42 36 Health Care Institute, Boston, USA. Dr. Sanita Hirunrassamee, Phramongkutklao Hospital, on September 26, 2021 by guest. Protected copyright. 43 37 Bangkok, Thailand, and Ms. Rosarin Sruamsiri and Dr. Nathorn Chaiyakunapruk, Naresuan 44 38 University, Phitsanulok, Thailand, provided helpful input on Thai essential medicines listings 45 39 and coverage policies. Mr. Amit Backliwal, at the time of the study at IMS Health, Bangkok, 46 40 Thailand, shared valuable insights on the Thai pharmaceutical market. 47 41 48 42 Author contributions: Laura Garabedian, Dennis Ross-Degnan and Anita Wagner designed the 49 43 study and developed the analytic approach. Peter Stephens assembled the data files. Laura 50 44 Garabedian analyzed the data. Sauwakon Ratanawijitrasin provided the Thai national list of 45 essential medicines and information on relevant Thai policies and context surrounding the 51 52 53 54 55 1 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 33 of 58 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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7 8 9 1 reform. All authors participated in the interpretation of the results. Laura Garabedian wrote the 10 2 first draft of the paper. All authors contributed to the writing of the manuscript. 11 3 12 4 Opinions expressed are solely those of the authors and not of the institutions they represent. 13 5 14 6 Competing Interest Statement: All authors have completed the Unified Competing Interest 15 7 form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) 8 and declare: LFG had financialFor support peer from Harvard Medical review School and Harvard University,only 16 9 AW and DRD were supported in part by a grant from the Novartis Foundation for Sustainable 17 10 Development, PS is an employee of IMS Health; no financial relationships with any 18 11 organisations that might have an interest in the submitted work in the previous 3 years; no other 19 12 relationships or activities that could appear to have influenced the submitted work. 20 21 13 Funding: IMS Health provided the data in-kind. The Harvard Medical School Fellowship in Formatted: Font: Bold 22 14 Pharmaceutical Policy Research and the Harvard University PhD Program in Health Policy 23 15 supported Ms. Garabedian. Drs. Wagner and Ross-Degnan were supported in part by a grant 24 16 from the Novartis Foundation for Sustainable Development to develop examples of research on 25 17 access to medicines using IMS Health data for presentation at the Third International Conference 26 18 for Improving Use of Medicines. 27 19 20 IRB Approval: Harvard Pilgrim Health Care Institute Office of Sponsored Programs 28 21 29 22 Exclusive Licence Statement: The Corresponding Author has the right to grant on behalf of all 30 23 authors and does grant on behalf of all authors, a worldwide licence to the Publishers and its 31 24 licensees in perpetuity, in all forms, formats and media (whether known now or created in the 32 25 future), to i) publish, reproduce, distribute, display and store the Contribution, ii) translate the 33 26 Contribution into other languages, create adaptations, reprints, include within collections and

34 27 create summaries, extracts and/or, abstracts of the Contribution, iii) create any other derivative http://bmjopen.bmj.com/ 35 28 work(s) based on the Contribution, iv) to exploit all subsidiary rights in the Contribution, v) the 36 29 inclusion of electronic links from the Contribution to third party material where-ever it may be 37 30 located; and, vi) licence any third party to do any or all of the above. 38 31 39 32 Data Sharing Statement: Data available upon request, at the approval of IMS Institute for 40 33 Healthcare Informatics. 41 34 42 on September 26, 2021 by guest. Protected copyright. 43 35 44 45 36 46 37 47 48 38 49 50 39 51 40 52 53 54 55 2 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 34 of 58 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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7 8 9 1 10 2 Article Summary 11 12 3 Article Focus 13 14 4 • Medicines present a key challenge to achieving universal coverage. 15 5 • Health insuranceFor systems have peerthe potential to improve review cost-effective use ofonly medicines, 16 6 yet there is little evidence about their impact on medicine use in low- and middle -income 17 7 countries. 18 8 • The recentrapid implementation of universal health coverage in Thailand presents a 19 9 unique opportunity to measure the impact of health insurance expansion and associated 20 10 physiciancapitated payment changes on utilization of medicines. 21 11 Key Messages 22 23 12 • Expanding health insurance coverage with a medicines benefit to the entire Thai 24 13 population increased access to medicines in primary care. 25 14 • The universal coverage scheme did not seem to have increased use of medicines for 26 15 diseases that are typically treated in secondary or tertiary care settings, or increased 27 16 generic market penetration. 28 17 • In the future, it will be important for countries to assess quality and equity of medicines 29 18 use as they pursue policies to achieve universal coverage. 30 19 Strengths and Limitations 31 32 20 • We used an interrupted time series design, the strongest quasi-experimental approach for 33 21 evaluating effects of interventions, increasing internal validity.

34 22 • It is impossible to examine population subgroups in national IMS Health market data, but http://bmjopen.bmj.com/ 35 23 we are reasonably confident that universal coverage scheme enrollees are responsible for 36 24 observed changes. 37 25 38 39 26 40 41 27 42 28 on September 26, 2021 by guest. Protected copyright. 43 44 29 45 46 30 47 31 48 49 32 50 33 51 52 34 53 54 55 3 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 35 of 58 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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7 8 9 1 10 2 ABSTRACT 11 12 3 Objective: In 2001, Thailand implemented the Universal Coverage Scheme (UCS), a public 13 14 4 insurance system covering primarily the poor and uninsured that aimed to achieve universal 15 5 access to health care, includingFor essential peer medicines, and toreview influence provider behaviorprimary only 16 6 care centers and hospitals to use resources efficiently, via capitated payment for outpatient 17 18 7 services and other payment policies for inpatient care. Our objective was to evaluate the impact 19 8 of the UCS on utilization of medicines in Thailand for three non-communicable diseases: cancer, 20 21 9 cardiovascular disease, and diabetes. 22 10 Design: Interrupted time series design, with a non-equivalent comparison group. 23 11 Setting: Thailand, 1998-2006. 24 25 12 Data: Quarterly purchases of medicines from hospital and retail pharmacies collected by IMS 26 13 Health between 1998 and 2006. 27 28 14 Intervention: UCS implementation, April-October 2001. Formatted: Font: Italic 29 15 Outcome measures: Total pharmaceutical sales volume and percent market share by licensing 30 31 16 status. and National Essential Medicine List (NEML) status. 32 17 Results: The UCS was associated with long-term increases in sales of medicines for conditions 33 18 that are typically treated in outpatient primary care settings, such as diabetes, high cholesterol

34 http://bmjopen.bmj.com/ 35 19 and high blood pressure, but not for medicines for diseases that are typically treated in secondary 36 20 or tertiary care settings, such as heart failure, arrhythmias, and cancer. While the majority of 37 38 21 increases in sales were for essential medicines, there were also significant post-policy increases 39 22 in sales of non-essential medicines. Immediately following the reform, there was a significant 40 23 shift in hospital sector market share by licensing status for most classes of medicines. 41 42 24 Government-produced products often replaced branded generic or generic competitors. on September 26, 2021 by guest. Protected copyright. 43 25 Conclusions: Our results suggest that expanding health insurance coverage with a medicines Formatted: Font: Bold 44 45 26 benefit to the entire Thai population increased access to medicines in primary care. However, our 46 27 study also suggests that the UCS may have had potentially undesirable effects. Evaluations of the 47 48 28 long-term impacts of universal health coverage on medicines utilization are urgently needed. 49 50 29 51 30 52 53 54 55 4 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 36 of 58 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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7 8 9 1 MANUSCRIPT 10 11 2 Introduction 12 3 13 14 4 Universal Health Coverage 15 5 In 2005, Member StatesFor of the World Healthpeer Organization review (WHO) made a commitment only to work 16 1 17 6 towards universal health care coverage. The 2010 WHO World Health Report provides a 18 7 roadmap for countries to achieve this goal.2 Universal coverage requires the restructuring of 19 8 health care and financing systems to improve access to health care services, reduce financial 20 21 9 hardship, and increase the efficiency and equity of the health system.2 22 10 23 24 11 Medicines, which consume 25–%–65% of total public and private spending on health in 3 25 12 developing countries, present a key challenge to achieving universal coverage. The high Formatted: Superscript 26 27 13 spending on, and inefficient use of, medicines threaten the financial sustainability of a universal 28 14 coverage scheme. According to the WHO, three of the top ten sources of health care inefficiency 29 15 involve medicines: high medicine prices and underuse of generics; use of substandard and 30 2 31 16 counterfeit medicines; and inappropriate and ineffective use of medicines. Health insurance 32 17 systems have several features (e.g., a defined population, access to utilization data, and financial 33 18 leverage) that give them a unique advantage to reduce out-of-pocket (OOP) expenditures and 34 http://bmjopen.bmj.com/ 35 19 improve the cost-effective use of medicines through active management strategies involving 36 20 medicines selection, purchasing, contracting (e.g., physician payment) and utilization 37 38 21 management.4 However, there is little evidence about the impact of health insurance on access to 39 22 and use of medicines in low- and middle-income countries (LMICs).4 40 41 23 42 24 The recent implementation of universal health coverage in Thailand presents a unique on September 26, 2021 by guest. Protected copyright. 43 44 25 opportunity to measure the impact of health insurance expansion and physicianhospital payment 45 26 changes (from fee-for-service to capitationthe majority of the population is now covered under a 46 27 closed-ended payment scheme5) on utilization of medicines. 47 48 28 49 29 Universal Health Coverage in Thailand 50 51 30 With the implementation of the UCS in 2001, Thailand became one of the first LMICs to achieve 52 31 universal coverage.5,6,7 The reformsreform preserved the formal sector workforce schemes: the 53 54 55 5 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 37 of 58 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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7 8 9 1 Social Health Insurance (SHI) scheme for private sector employees (6·37·2% of the total 10 2 population in 2001) and the Civil Service Medical Benefit Scheme (CSMBS) for government 11 7 8 12 3 employees and their dependents (13·6%). In addition, the8·5%). The UCS covered those 13 4 previously enrolled in a voluntary health card (VHC) scheme (22·020·8%), in private health 14 15 5 insurance (2·1·6%), or inFor a tax-based, means-testedpeer Low Incomereview Scheme (LIS) for theonly poor, 8,9 7,8 16 6 elderly, children and disabled (28·32·4%) %) as well as more than one quarter (26·629·0%) of Formatted: Superscript 17 7 the population without previous insurance.78 The UCS was rolled out to all provinces between 18 56 19 8 April and October 2001. By 20052004, 95·5% of the population was insured, with just over 20 9 70%three-quarters (75.2%) of the population covered by the UCS.76 21 22 10 23 11 In addition to coverage expansion, the reform also dramatically altered the mechanism for 24 12 hospital payment. Before the reform, hospitals were accustomed to fee-for-service (FFS) 25 26 13 payments from most insurance schemes, aside from SSI, and the uninsured, who paid OOP per 27 14 service (i.e., user fees).10 The majority of user fee spending was on medicines.11 After the 28 29 15 reform, FFS payment only applied to CSMBS patients and for the majority of patients, now UCS 30 16 enrollees, hospitals were paid on a closed-ended basis5 for all covered services, including 31 32 17 medicines. 33 18

34 19 The UCS is a compulsory, tax-financed scheme with comprehensive coverage of inpatient and http://bmjopen.bmj.com/ 35 56 36 20 outpatient services, including medicines on the National List of Essential Medicines (NLEM). Formatted: Superscript 56 37 21 Individuals must enroll in the scheme at a local Contracting Unit for Primary Care (CUP), Formatted: Superscript 38 912 39 22 primarily housed in government-owned hospitals. Each CUP receives a capitated payment per 56 40 23 registered member to provide outpatient services and medicines. CUPs initially served as gate- Formatted: Superscript 41 24 keepers for secondary and tertiary hospitals. When At the beginning of the scheme, when 42 on September 26, 2021 by guest. Protected copyright. 43 25 patients were referred, diagnosis-related payments (DRG) for higher-level care initially camehad 44 26 to come out of the CUP’s capitated payment, so CUPs had a financial disincentive to refer 45 56 46 27 patients. Shortly after the reform was implemented, a separate fund (i.e., a global budget) for 47 28 inpatient services was created, which likely reduced disincentives to refer created by the 48 6 49 29 capitated payment scheme. A capitated payment also creates financial incentives for use of 50 30 lower cost medicines (e.g., generics or less expensive therapeutic alternatives). Formatted: Font color: Red 51 31 52 53 54 55 6 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 38 of 58 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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7 8 9 1 Our objective was to evaluate the immediate, short-term (one year) and long-term (five year) 10 2 impacts of the UCS on pharmaceutical market size and composition for medicines for three non- 11 12 3 communicable diseases (NCDs): cancer, cardiovascular disease, and diabetes. We hypothesized 13 4 that the UCS would result in a gradual increase in sales volume, particularly of products used in 14 15 5 primary care, as enrollmentFor into the Schemescheme peer increased review, and inlikely made accessonly to health 16 6 services and medicines more affordable for the majority of the population. We also hypothesized 17 7 that there would be an immediate increaseshift in market share offrom more expensive brand 18 19 8 name to less expensive generic or branded generic products and to medicines on the NLEM in 20 9 response to capitated paymentclosed-ended budget rules. We focused on medicines for NCDs 21 10–13 13– 22 10 since these illnesses represent a large and growing health care burden in Thailand Thailand 23 11 16 and other LMICs14LMICs17 and most, but not all, medicines for NCDs would be prescribed 24 12 and dispensed in primary care settings. 25 26 27 13 Methods 28 14 Data 29 15 We used data on quarterly pharmaceutical sales in Thailand from 1998 to 2006 provided by IMS 30 1518 31 16 Health. The sales data are generated from reports to IMS Health by multinational 32 17 pharmaceutical companies and surveys of purchases by hospital and retail pharmacies. IMS 33 18 surveys approximately 200 hospitals (including general and specialized, public and private) and 34 http://bmjopen.bmj.com/ 35 19 350 retail pharmacies in Thailand, and employs. These facilities constitute a stratified random 36 20 sample of these facilities that enablesthe over 1,100 hospitals and 14,000 retail pharmacies in 37 38 21 Thailand to enable national projections. Documentation on the IMS data collection and 39 22 validation process is available upon request from the authors. Medicines were classified 40 41 23 according to the European Pharmaceutical Research Association (EphMRA) Anatomical 42 16 19 24 Therapeutic Chemical (ATC) system. on September 26, 2021 by guest. Protected copyright. 43 44 25 45 26 Outcomes 46 27 We used two outcome measures: total volume and percent market share. Total volume is the 47 48 28 number of standard units purchased per capita per quarter (i.e., “sales”). We analyzed total 49 29 volume by sector (i.e., retail versus hospital) and, within the hospital sector, by NLEM versus 50 51 30 non-NLEM status of medicines (based on the 1999 Thai NLEM).). A standard unit, as defined by 52 31 IMS Health, is the smallest dose of a product, which equates to one tablet or capsule for an oral 53 54 55 7 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 39 of 58 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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7 8 9 1 dosage form, one teaspoon (5ml) for a syrup, and one ampoule or vial for an injectable product. 10 2 WeFor the total volume analyses, we divided total volume by size of the population over 15 11 12 3 years old to control for population growth (using yearly population estimates from the World 13 4 Bank17Bank20). We used the entire population as denominator for insulins, since they are also 14 15 5 used for Type 1 diabetes,For a chronic disease peer that affects children.review Percent market share only is the Formatted: Font: 12 pt 16 6 percent of total volume in four mutually exclusive categories of licensing status: originator brand 17 7 products, branded generic products (products sold under a brand name other than the originator 18 19 8 brand name of the molecule), generic products (products that are sold under the generic molecule 20 9 name), and products manufactured by Thailand’s Government Pharmaceutical Organization 21 22 10 (GPO). We also assessed percent market share by NLEM status (based on the 1999 and 2004 23 11 Thai NLEM). 24 12 25 26 13 We analyzed total volume and market share for medicines in eight therapeutic classes: two 27 14 classes of diabetes products (oral antidiabetics and insulins), three classes of cardiovascular 28 29 15 disease products (antihypertensives, lipid-regulating, and cardiac therapy products) and three 30 16 classes of cancer products (antineoplastics, immunostimulating agents, and cytostatic hormone 31 32 17 therapy products); Table 1 in the online appendix lists all medicines by ATC code. We assigned 33 18 each therapeutic class to one of two categories: medicines usually used to treat primary care

34 19 health conditions and medicines usually used to treat more complicated conditions, typically in http://bmjopen.bmj.com/ 35 36 20 secondary/tertiary, often inpatient care, settings. Antidiabetic, insulin, antihypertensive and lipid- 37 21 lowering products are usually used for conditions that are typically treated in primary care 38 39 22 settingsconditions (i.e., diabetes, high blood pressure and high cholesterol), whereas cardiac 40 23 therapy and cancer products are usually used for more severe conditions that are more likely to 41 24 be treatedrequire treatment by a specialist and/or in an inpatient settings.setting. 42 on September 26, 2021 by guest. Protected copyright. 43 25 44 26 Research Design 45 46 27 We used an interrupted time series design, the strongest quasi-experimental approach for 47 28 evaluating effects of interventions, which has been used extensively for medication use 48 1821 49 29 research. Although we did not have an equivalent control group, we used medicines sold in 50 30 the retail sector as a non-equivalent comparison group,1922 assuming that the retail market should 51 52 53 54 55 8 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 40 of 58 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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7 8 9 1 be relatively unaffected by the reforms since UCS enrollees could only obtain covered medicines 10 2 through their local, hospital-based CUP. 11 12 3 13 4 Statistical Analysis 14 15 5 The intervention was theFor UCS roll-out peerfrom April to October review 2001. We defined three only distinct 16 6 periods: 12 quarters pre-reform (1998Q2-2001Q1), a 3-quarter UCS roll-out period (2001Q2- 17 7 2001Q4; grey box in figures), and 19 quarters post-reform (2002Q1-2006Q3). We dropped Formatted: Font: Not Bold, Not Italic, 18 (Asian) Chinese (PRC) 19 8 2006Q4 from theended analysis prior to 2006Q4 since there was a policy change at thisthat time 20 9 (the removal of an initial 30 Baht co-payment per visit) thatwhich may have impacted outcomes. 21 22 10 In sensitivity analyses, we extended the intervention roll-out period through 2002 and through 23 11 2003 to account for potentially delayed implementation and lag of actual enrollment into the 24 12 scheme. 25 26 13 27 14 We used segmented linear regression to measure the pre-reform trend, the immediate level Formatted: Add space between 28 paragraphs of the same style, No 29 15 change following the intervention period, and the post-reform change in trend (as compared to widow/orphan control, Don't adjust space between Latin and Asian text, Don't adjust 30 16 the pre-reform trend). For the NLEM analysis, we reclassified NLEM status in 2005Q1 (when space between Asian text and numbers 31 32 17 the 2004 list was implemented) and included a pre-post term (“NLEM”) in the model to account 33 18 for possible discontinuity due to the reclassification. We report two estimates from the

34 19 segmented regression models – the post-reform change in trend and the immediate level change http://bmjopen.bmj.com/ 35 36 20 following the reform. We controlled for serial autocorrelation using an autoregressive error 37 21 model. We retained all terms in the models, even if non-significant. We used the models to 38 2023 39 22 estimate absolute and relative differences (with 95% confidence intervals) in observed versus 40 23 predicted total volume at one year and five years post-reform. In sensitivity analyses, we 41 24 included a quadratic term for the post-reform trend and used a likelihood ratio test to determine 42 on September 26, 2021 by guest. Protected copyright. 43 25 the best-fitting model. We report below results from the best-fitting model of the shortest (i.e., 3 Formatted: Font: Bold 44 26 quarter) intervention period and mention differences in model results where they existed. Results 45 46 27 from sensitivity analyses are available upon request. We used the AUTOREG procedure in SAS 47 28 9.23 for all analyses. Formatted: Font color: Red 48 49 29 50 51 30 Results 52 31 Formatted: Font color: Auto 53 54 55 9 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 41 of 58 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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7 8 9 1 Hospital Sector Volume 10 2 The majority of sales in Thailand for all cancer, cardiovascular disease and diabetes medicines 11 12 3 studied were in the hospital sector and were for medicines on the NLEM. After implementation Formatted: Font color: Auto 13 4 of the UCS, there was a significant increase in level of sales of insulins and a significant increase Formatted: Font: Italic 14 15 5 in trend in sales of antidiabetic,For insulin, peer antihypertensive, review lipid regulating, and cytostatic only Formatted: Font: Italic 16 6 hormone products [Table 1, Figures 1 and 2]. There was a significant reduction in level of sales Formatted: Font: Italic 17 7 immediately following the reforms for three medication classes: antihypertensive, cardiac 18 19 8 therapy and immunostimulating agents (although only the latter was significant in the sensitivity 20 9 analyses using a longer intervention period). ) [Table 1, Figures 1 and 2]. 21 22 10 23 11 The UCS was associated with increased sales of diabetes medicines. One year after the policy, 24 12 the sale of insulin was 35% (95% CI: 15%, 55%) higher and, at five years, 174% (95% CI: 25 26 13 114%-235%) higher than what would have been expected in the absence of the UCS [Table 2]. 27 14 The increase in insulin sales was driven primarily by human insulins, which are on the NLEM 28 29 15 and marketed as branded generics by two manufacturers. The policy was associated with a 39% 30 16 (95% CI: 14%, 64%) increase in antidiabetic product sales five years after implementation 31 32 17 [Table 2]. This iswas largely due to increased sales of generic and branded generic metformin 33 18 and glibenclamide products, both of which are on the NLEM.

34 19 http://bmjopen.bmj.com/ 35 36 20 Implementation of the UCS appears to have had a mixed impact on sales of cardiovascular 37 21 medicines. Five years after the policy, the sale of lipid lowering agents was nearly double (108% 38 39 22 increase; 95% CI: 60%, 157%) what would have been expected in the absence of the scheme 40 23 [Table 2]. The increase was primarily due to sales of branded generic simvastatin and 41 24 gemfibrozil products, which are on the NLEM, and a small but steady increase in sales of 42 on September 26, 2021 by guest. Protected copyright. 43 25 originator atorvastatin products, which arewere not on the NLEM until 2004. For 44 26 antihypertensives, the significant increase in post-policy trend compensated for an initial drop in 45 46 27 sales, resulting in a slight increase in sales five years after the policy (19% increase; 95% CI: - 47 28 3%, 40%). The increased trend was primarily due to sales of enalapril, atenolol, and amlodipine, 48 49 29 all of which are on the NLEM and predominately sold as branded generics. The reform had no 50 30 significant impact on sales of cardiac therapy medicines one or five years after the policy. 51 31 52 53 54 55 10 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 42 of 58 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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7 8 9 1 The results were also mixed for cancer medicines. The UCS had no significant one- or five-year 10 2 impact on the sale of antineoplastics or cytostatic hormones (although the latter class did 11 12 3 experience a significant post-policy increase in trend). However, the policy was associated with 13 4 an immediate reduction in sales of immunostimulating agents that did not recover in the post- 14 15 5 policy period. One year Forafter implementation, peer the sale of reviewimmunostimulating agents only was 35% 16 6 (95% CI: -45%, -25%) lower than expected from pre-policy trends, and 26% lower (95% CI: - 17 7 45%, -8%) five years post-policy. This drop is almost entirely due to a sharp reduction in sales of 18 19 8 interferon alfa-2b, a non-NLEM medicine, around the time of UCS implementation, which could 20 9 have been due to a co-incidentalcoincidental recall of an interferon alfa-2b product.21 24 21 22 10 23 11 There was mixed evidence about the effects of the UCS on utilization of NLEM medicines. For 24 12 all classes that experienced a post-policy increase in trend, there was an increase in sales of both 25 26 13 NLEM medicines (except for cytostatic hormones) and non-NLEM products [see online 27 14 appendix, Table 3]. The immediate decrease in sales of cardiac therapies and immunostimulating 28 29 15 agents was largely due to a decrease in non-NLEM medicines. However, for these two classes, 30 16 there was no corresponding increase in NLEM medicines. 31 32 17 33 18 Finally, as expected, the reform had little impact on sales volume in the retail sector – there were

34 19 few significant post-implementation changes, and the changes that were significant were small in http://bmjopen.bmj.com/ 35 36 20 magnitude [see online appendix, Table 2]. 37 21 38 39 22 Hospital Sector Market Share 40 23 Immediately following the reform, there were significant shifts in hospital sector market share by 41 24 licensing status for most classes [Table 3]. The changes for antidiabetics and cardiac medicines - 42 on September 26, 2021 by guest. Protected copyright. 43 25 the two therapeutic classes with the largest shifts – were due to significant increases in GPO- 44 26 produced medicines, primarily at the expense of branded generics and, to a lesser extent, 45 46 27 generics. There was a significant increase in GPO antidiabetic products (+16% of market; 95% 47 28 CI: 12%, 20%), and decreases in branded generic (-12%; 95% CI:-16%, -9%) and generic (-4%; 48 49 29 95% CI: -6%,-1%) products immediately after the policy [Figure 3]. Similarly, there was a 50 30 significant increase in GPO cardiac therapy products (+22%; 95% CI: 15%, 28%), and 51 31 significant decreases of branded generic (-14%; 95% CI:-21%, -7%) and generic (-4%; 95% CI:- 52 53 54 55 11 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 43 of 58 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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7 8 9 1 6%, -2%) products immediately after the policy [Figure 4]. There was also a small decrease in 10 2 market share of generic antihypertensives (-6%; 95% CI: -8%, -3%), which was compensated for 11 12 3 by a marginally significant increase in GPO products. 13 4 14 15 5 The market for lipid regulatingFor agents peerexperienced an immediate review shift from originator only products (- 16 6 8% market share; 95% CI: -:-10%, -5%) to branded generics (+8%; 95% CI: 5%, 10%). A 17 7 similar shift was seen for in the market for immunostimulating agents (6% decrease in originator 18 19 8 products [95% CI:-10%, -3%] and a 5% increase in branded generics [95% CI:2%, 7%]). The 20 9 cytostatic hormone market experienced an immediate shift from branded generic (-8%; 95% CI:- 21 22 10 12%, -4%) to generic products (+6%, 95% CI: 1%, 11%). Generic insulins experienced a slight 23 11 decrease in market share caused by the market exit of the sole generic manufacturer just prior to 24 12 the policy. There were no immediate changes in market share for antineoplastics. Aside from the 25 26 13 immediate level changes following the policy, there were few major changes in market share for 27 14 all classes. Formatted: Font color: Auto 28 29 15 The UCS did not have a major impact on NLEM market share, likely because the share of 30 16 NLEM medicines was already quite high [see online appendix Table 6 and Figure 17]. The only 31 32 17 notable level change, for immunostimulating agents, was likely due to the coincidental recall of a 33 18 non-NLEM interferon alfa-2b product.24 While all medicine classes had significant post-reform

34 19 trends, these trends were small in magnitude and NLEM market share remained fairly stable over http://bmjopen.bmj.com/ 35 36 20 the study period until the 2004 NLEM was introduced. There were large changes in NLEM 37 21 market share for three classes – antihypertensives, lipid regulating agents and cytostatic 38 39 22 hormones – at the time of the 2004 NLEM implementation in 2005Q1 [see online appendix 40 23 Table 6 and Figure 17]. Given the increase in post-reform volume for many medicine classes, a 41 24 stable NLEM market share in the short-term (i.e., pre-2005) following the UCS implementation 42 on September 26, 2021 by guest. Protected copyright. 43 25 suggests a post-reform increase in both NLEM and non-NLEM medicines. 44 26 45 46 27 Discussion 47 28 The UCS was associated with long-term (i.e., 5 year) increases in hospital sector sales of 48 49 29 medicines for chronic diseases that are usually treated in primary care settings, such as diabetes, 50 30 high blood pressure, and high cholesterol. We hypothesized this gradual increase in 51 31 volumevolumes since the UCS expanded access to primary care7care25 and actual enrollment into 52 53 54 55 12 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 44 of 58 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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7 8 9 1 the scheme occurred gradually from implementation in 2001 until around 20052004, by which 10 2 time 95·5% of the population had insurance coverage.76 The UCS, which radically changed 11 12 3 hospital financing and reimbursement, was also associated with an immediate market shift to 13 4 locally produced or branded generic products for most therapeutic classes. 14 15 5 For peer review only 16 6 Despite these increases in access, the policy did not appear to increase sales of medicines for 17 7 more severe diseases like heart failure, arrhythmias, and cancer, which are often treated in 18 19 8 secondary or tertiary settings. This finding is in lineconsistent with evidence that the capitated 20 9 payment system initially discouraged referrals of UCS patients to higher-level care.5,7,226,25,26 The 21 22 10 UCS also appears to have had a mixed impact on utilization of essential medicines. There were 23 11 increases in NLEM medicines, which are covered, as well as non-NLEM medicines. Similarly, 24 12 given the capitated UCS payment system, we expected to see an increase in sales of generic 25 26 13 medicines, which are typically less expensive. However, the majority of sales in most classes 27 14 were for branded generic products, many of which had generic alternatives in the market. 28 29 15 Interestingly, substantial market share shifts occurred toward products manufactured by the Thai 30 16 GPO, which by law received preferential status by hospital purchasers.23 GPO products have 31 24 25 32 17 been noted to have higher than market prices and sometimes to be of substandard quality. have 33 18 been noted to have higher than market prices.27 By law, GPO products received preferential

34 19 status by hospital purchasers,28 which negates the incentive to prescribe cheaper alternatives http://bmjopen.bmj.com/ 35 36 20 under the capitated payment system. While the increase in GPO products and the UCS 37 21 implementation may be a coincidence in timing, it is noteworthy that the GPO expanded its 38 39 22 product line at a time when the UCS policy expanded the market of people who could afford 40 23 medicines. 41 24 42 on September 26, 2021 by guest. Protected copyright. 43 25 Our study demonstrates the value of IMS Health market intelligence data for rigorous health 44 26 policy evaluation. Unlike other sources of data on pharmaceutical utilization (i.e., national health 45 46 27 surveys or ad hoc hospital surveys), IMS data represent country pharmaceutical markets 47 28 consistently over time and are useful for the evaluation of system-wide interventions. 48 49 29 Nevertheless, the data pose some limitations. Aggregate national sales data do not allow us to 50 30 determine whether observed increases in medicines sales occurred preferentially among UCS 51 31 enrollees or enrollees in the SHI and CSMBS schemes, conceivably to compensate for financial 52 53 54 55 13 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 45 of 58 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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7 8 9 1 strain of the UCS on hospital budgets.56 CSMBS expenditures increased following UCS 10 2 implementation26implementation29 and increased medicines sales among CSMBS enrollees, 11 12 3 reimbursed on a fee-for-service basis, could explain increases in non-NLEM medicines and 27 5 13 4 medicines with less expensive therapeutic alternatives. However, it is unlikely that increased 14 15 5 utilization among CSMBSFor enrollees explainspeer most of the reviewobserved volume changes onlysince it 16 6 would imply that one-quarter (for diabetes) to one-third (for hypertension) of CSMBS members 17 7 were on these treatments and the change in utilization would have needed to be coincident with 18 19 8 the initiation of the UCS.this would imply that one-half (for diabetes) to three-quarters (for 20 9 hypertension) of CSMBS members (7.1% of the total population in 20046) were on these 21 22 10 treatments in 2004. Even the CSMBS and SSI schemes combined (20.3% of the total population 23 11 in 20046) are unlikely to be responsible for the observed changes since this would imply that 24 12 one-quarter (for diabetes) and one-third (for hypertension) of enrollees in the two schemes were 25 26 13 on these treatments in 2004. These estimates are much higher than the national prevalence (6.7% 27 14 for diabetes30 and 22.0% for hypertension31 in 2004) and unlikely in the civil servant and private 28 29 15 sector workforce populations, which are likely to be healthier and wealthier than the national 30 16 average. 31 32 17 33 18 Our interpretation of the observed changes assumes that pharmaceutical sales to hospital and

34 19 retail pharmacies reflected total market utilization, and that hospital sales volumes included http://bmjopen.bmj.com/ 35 36 20 utilization at affiliated primary care units. This assumption seems justified in light of the 37 21 estimated 91% accuracy of IMS Health data in representing the Thai pharmaceutical market.2832 38 39 22 For local generic products, including those produced by the GPO, IMS Health data isare based 40 23 on pharmacy surveys only (as opposed to pharmacy surveys and manufacturer reports), so we 41 24 may have underestimated utilization. However, unless this systematic underestimation changed 42 on September 26, 2021 by guest. Protected copyright. 43 25 at the point of the UCS implementation, it would not have impacted our results. Finally, since we 44 26 did not convert standard units of product sold to defined daily doses (DDD), we do not describe 45 46 27 sales changes in terms of average adult doses. 47 28 48 49 29 There are also potential limitations due to study design and statistical analysis. We addressed the 50 30 main threat to the internal validity of the interrupted time series design -– a concurrent event that 51 31 affects the outcome of interest -– by assessing other policies or market events that occurred at the 52 53 54 55 14 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 46 of 58 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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7 8 9 1 time of the UCS, through literature reviews, discussions with in-country experts, and by 10 2 including the retail sector as a comparison. The statistical approach, segmented regression 11 12 3 analysis, usually assumes a linear trend and well-defined break point. Sensitivity analyses that 13 4 varied model specification and intervention duration did not change the findings. By reporting 14 15 5 results from fully-specifiedFor models, we peer may have underestimated review the statistical significance only of 16 6 one- and five-year change estimates. 17 7 18 19 8 While both the context and the implementation of universal coverage in Thailand are unique and 20 9 not necessarily generalizable to other LMICs, our findings suggest that expanding health 21 22 10 insurance coverage with a medicines benefit to the entire population, together with changes in a 23 11 LMICthe payment system and increased thelocal manufacturing, increased the per capita volume 24 12 of medicines sold and, by inference, improved access to medicines in the primary care sector in 25 26 13 Thailand, presumably by making medicines more affordable. Since the study period, Thailand 27 14 has enacted further policies to address pharmaceutical sector cost escalation (e.g., strict 28 29 33 29 15 enforcement of reimbursement for only NLEM medicines in the CSMBS CSMBS ) and to 30 16 ensure appropriate access to non-NLEM medicines (e.g., coverage of medicines for HIV, renal 31 30–3234–36 32 17 replacement therapy, and mental health conditions). In the future, it will be important for 33 18 Thailand and other countries to assess equity in access to and quality of use of medicines use,

34 19 availability of medicines in health centers and hospitals, out-of-pocket and system expenditures http://bmjopen.bmj.com/ 35 36 20 and affordability, and health outcomes as they pursue policies to achieve universal coverage. 37 21 38 39 22 40 23 41 24 42 on September 26, 2021 by guest. Protected copyright. 43 25 44 26 45 46 27 47 28 48 49 29 50 30 51 31 52 53 54 55 15 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 47 of 58 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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7 8 9 1 10 2 11 12 3 13 4 Formatted: Font: Bold 14 15 5 For peer review only 16 6 Formatted: Default Paragraph Font, Font: Not Bold 17 7 18 Formatted: Normal 19 8 Formatted: Normal, Line spacing: 1.5 lines 20 9 21 Formatted: Font: Bold 22 10 23 11 24 12 25 26 13 27 14 28 29 15 30 16 31 32 17 33 18

34 http://bmjopen.bmj.com/ 19 References Formatted: Space After: 0 pt, Line 35 spacing: 1.5 lines 20 1 World Health Organization. Resolution from the fifty-eight World Health Assembly. 36 Formatted: Font: Not Bold 21 Sustainable health financing, universal coverage and social health insurance (WHA58.33) 37 Formatted: Font: Not Bold 38 22 [Internet]. 2005 [cited 2011 Mar 8]. Available from: 39 23 http://www.who.int/providingforhealth/topics/WHA58_33-en.pdf. 40 24 25 2 World Health Organization. 2010 World Health Report: Health systems financing: the 41 26 path to universal coverage [Internet]. 2010 [cited 2011 Mar 8]. Available from: Formatted: Font: Not Italic 42 27 http://www.who.int/whr/2010/en/index.html. on September 26, 2021 by guest. Protected copyright. 43 28 44 29 3 J. Quick,. Ensuring access to essential medicines in developing countries—A framework 45 30 for action. Clinical Pharmacology and Therapeutics. 2003; 73(4): 279–283. Formatted: Font: Italic 46 31 47 32 4 Faden L, Vialle-Valentin C, Ross-Degnan D, Wagner A. Active pharmaceutical 48 33 management strategies of health insurance systems to improve cost-effective use of 49 34 medicines in low- and middle-income countries: a systematic review of current evidence. 50 35 Health Policy. 2011; 100(2-3): 134-143. 51 36 Formatted: Indent: Left: 0", Hanging: 52 0.5" 53 54 55 16 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 48 of 58 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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7 8 9 1 10 2 1215 World Health Organization. Thailand: Health Profile [Internet]. 2011 Apr 11 [cited 2012 11 3 Feb 8]. Available from: http://www.who.int/gho/countries/tha.pdf 12 4 13 5 1316 Porapakkham Y, Rao C, Pattaraarchachai J, et al. Estimated causes of death in Thailand, 14 6 2005: implications for health policy. Population Health Metrics. 2010; 8(1): 14. 15 7 8 1417 Beaglehole R, BonitaFor R, Horton peer R, et al. Priority actionsreview for the non-communicable only 16 9 disease crisis. Lancet. 2011; 377(9775): 1438-1447. 17 10 Formatted: Space Before: 0.1 pt, After: 18 11 1518 IMS Health MIDAS. 1998-2006. 0.1 pt 19 12 20 13 1619 European Pharmaceutical Market Research Association (EphMRA). Anatomical Formatted: Space Before: 0.1 pt, After: 21 14 Classification [Internet]. 2012 [cited 2012 Feb 6]. Available from: 0.1 pt 22 15 http://www.ephmra.org/classification/anatomical-classification.aspx 23 16 24 17 1720 The World Bank. Data [Internet]. 2011 [cited 2011 May13]. Availalble from: 25 18 http://data.worldbank.org/ 26 19 Formatted: Normal, Indent: Left: 0", 27 20 1821 Wagner AK, Soumerai SB, Zhang F, Ross-Degnan D. Segmented regression analysis of Hanging: 0.5" 28 21 interrupted time series studies in medication use research. J Clin Pharm Ther. 2002; 29 22 27(4): 299-309. 30 23 31 24 1922 Shadish WR, Cook TD, Campbell DT. Experimental and quasi-experimental designs for 32 25 generalized causal inference. Boston: Houghton Mifflin Company; 2002. 33 26 Formatted: Normal, Indent: Left: 0", 27 2023 Zhang F, Wagner AK, Soumerai SB, Ross-Degnan D. Methods for estimating confidence Hanging: 0.5"

34 http://bmjopen.bmj.com/ 28 intervals in interrupted time series analyses of health interventions. J Clin 35 29 Epidemiol.ClinEpidemiol. 2009; 62(2): 143-148. 36 30 Formatted: Indent: Left: 0", Hanging: 37 31 2124 United States. Food and Drug Agency. Recall of Interferon alfa-2b, (Recombinant), 0.5" 38 32 Powder for Injection, Intron A - (Schering Corporation) [Internet]. 2001 Oct 22 [cited 13 Formatted: Space Before: 0.1 pt, After: 39 33 Oct 2011]. Available from: 0.1 pt 40 34 http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandAp 41 35 proved/ApprovalApplications/TherapeuticBiologicApplications/ucm113617.htm 42 36 Formatted: Endnote Text, Indent: Left: on September 26, 2021 by guest. Protected copyright. 43 37 0", Hanging: 0.5" 44 38 25 Damrongplasit K, Melnick GA. Early results from Thailand's 30 Baht Health Reform: 45 39 something to smile about. Health Aff (Millwood). 222009;28(3):w457-466. 46 40 47 41 26 Yiengprugsawan V, Carmichael G, Lim L, Seubsman S, Sleigh A. Explanation of 48 42 inequality in utilization of ambulatory care before and after universal health insurance in 49 43 Thailand. Health Policy Plan. 2011; 26(2): 105-14. 44 Formatted: Normal, Indent: Left: 0", 50 Hanging: 0.5" 51 45 27 Ten Kate D. Safe at any costs? Asia Sentinel (Hong Kong) [Internet].23 2001 Jan 4 [cited 46 2012 Feb 6]. Available from: Formatted: Font: 12 pt, Not Italic 52 53 54 55 18 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 50 of 58 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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7 8 9 1 http://www.asiasentinel.com/index.php?option=com_content&task=view&id=351&Itemi 10 2 d=392 11 3 12 4 28 Ratanawijitrasin S. Pharmaceutical policy in Thailand: a review of three decades of Formatted: Space Before: 0.1 pt, After: 0.1 pt 13 5 government interventions. In: Eggleston K, editor. Prescribing cultures and 14 6 pharmaceutical policy in the Asia Pacific. Stanford: The Walter H. Shorenstein Asia- 15 7 Pacific ResearchFor Center Books; peer 2009. p. 79–106. review only 8 Formatted: Indent: Left: 0", Hanging: 16 9 24 Ten Kate D.29 Safe at any costs? Asia Sentinel (Hong Kong) [Internet]. 2001 Jan 4 0.5", Space Before: 0.1 pt, After: 0.1 pt 17 10 [cited 2012 Feb 6]. Available from: Formatted: Font: 12 pt, Not Italic 18 11 http://www.asiasentinel.com/index.php?option=com_content&task=view&id=351&Itemi 19 12 d=392 20 13 21 14 25 Bates, R. Local pharmaceutical production in developing countries: How economic 22 15 protectionism undermines access to quality medicines. Campaign for Fighting Diseases 23 16 discussion paper no. 1 [Internet]. 2008 Jan [cited Feb 7 2012]. Available from: 24 17 http://www.policynetwork.net/sites/default/files/local_drug_production.pdf . 25 18 26 19 26 Tangcharoensathien V, Jongudomsuk P. From policy to implementation: Historical Formatted: Space Before: 0.1 pt, After: 27 20 events during 2001-2011 of universal coverage in Thailand. Bangkok, Thailand: 0.1 pt 28 21 National Health Security Office; 2012. 29 22 Formatted: Endnote Text, Indent: Left: 23 27 Hirunrassamee S, Ratanawijitrasin S. Does your health care depend on how your insurer 0", Hanging: 0.5", Space Before: 0.1 pt, 30 24 pays providers? Variation in utilization and outcomes in Thailand. Int J Health Care After: 0.1 pt 31 25 Finance Econ. 2009; 9(2): 153-168. 32 26 33 27 2830 Aekplakorn W, Abbott-Klafter J, Premgamone A, et al. Prevalence and management of

34 28 diabetes and associated risk factors by regions of Thailand: Third National Health http://bmjopen.bmj.com/ 35 29 Examination Survey 2004. Diabetes Care. 2007;30:2007–2012 36 30 37 31 31 Aekplakorn W, Abbott-Klafter J, Khonputsa P, Tatsanavivat P, Chongsuvivatwong V, 38 32 Chariyalertsak S, et al. Prevalence and management of prehypertension and hypertension 39 33 by geographic regions of Thailand: the Third National Health Examination Survey, 2004. 40 34 J Hypertens. 2008; 26:191–198. 41 35 42 36 32 IMS Health. IMS Thailand Market Prognosis. 2012. Formatted: Space Before: 0.1 pt, After: on September 26, 2021 by guest. Protected copyright. 43 37 0.1 pt 38 2933 IMS Health. Pharma Pricing and Reimbursement. 2011 Mar; 16(3). Formatted: Indent: Left: 0", Hanging: 44 0.5", Space Before: 0.1 pt, After: 0.1 pt 45 39 40 3034 Khanna R. Universal Health Coverage in Thailand: What Lessons Can India Learn? Formatted: Space Before: 0.1 pt, After: 46 0.1 pt 47 41 [Internet]. 2010 Dec 16 [cited 2012 Feb 7]. Available from: 42 http://www.mfcindia.org/main/bgpapers/bgpapers2011/am/bgpap2011r.pdf Formatted: Normal, Indent: Left: 0", 48 Hanging: 0.5" 49 Formatted: Space Before: 0.1 pt, After: 0.1 pt 50 43 3135 Treerutkuarkul A. Thailand: health care for all, at a price. Bull WorldBullWorld Health 51 44 Organ. 2010; 88(2): 84-5. 52 45 53 54 55 19 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 51 of 58 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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7 8 9 1 3236 Pitayarangsarit S. The Introduction of the Universal Coverage of Health Care Policy in Formatted: Space Before: 0.1 pt, After: 10 2 Thailand: Policy Responses [PhD thesis]. London, UK: London School of Hygiene and 0.1 pt 11 3 Tropical Medicine; 2004 [cited 2012 Feb 7]. Available from: Formatted: Font: Not Italic 12 4 http://www.nhso.go.th/eng/download/The%20Introduction%20of%20the%20Universal% 13 5 20Coverage%20of%20Health%20Care%20Policy%20in%20Thailand_%20Policy%20Re 14 6 sponses.pdf 15 7 8 For peer review only 16 9 17 10 18 11 19 12 20 13 21 14 22 15 23 16 24 17 25 18 26 19 27 20 28 21 29 22 30 23 31 24 32 25 26 33 27

34 http://bmjopen.bmj.com/ 28 35 29 36 30 37 31 38 32 39 33 40 34 41 35 42 36 on September 26, 2021 by guest. Protected copyright. 43 37 44 38 45 39 46 40 47 41 48 42 49 43 TABLES44 50 45 51 52 53 54 55 20 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 52 of 58 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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7 8 9 Table1 1. Summary of the Impact of the Universal Coverage Scheme on Volume in the Hospital 10 Sector2 (from segmented regression results) * 11 Therapeutic Area Pre-policy trend Immediate change after Post-policy trend change 12 policy 13 14 DIABETES 15 Antidiabetics** For peer review only 16 Insulins** 17 18 CARDIOVASCULAR DISEASE 19 Antihypertensives 20 Lipid Regulating Agents** 21 Cardiac Therapy 22

23 CANCER 24 25 Antineoplastics 26 Cytostatic Hormones 27 Immunostimulating Agents** 28 *Arrows3 signify a statistically significant coefficient (p<0.05) from segmented regression with linear post-policy trend term, unless noted otherwise. **Quadratic4 model (which has a squared post-policy trend term) fits better than linear model. 29 Note:5 See online appendix Table 2 and Figures 1-8 for regression coefficients and figures for all therapeutic areas. 30 6 31 7 32Table8 2. Relative Impact of UCS on Sales of Medicines by Class (one and five years post policy)* 33 Therapeutic Class One Year Impact (in standard units) Five Year Impact (in standard units)

34 Predicted Observed Relative Change Predicted Observed Relative Change http://bmjopen.bmj.com/ 35 (95% CI) (95% CI) 36 Antidiabetics 2602·91 2769·79 6·4% (-6·9, 19·7) 3669·13 5090·62 38·7% (13·5, 64·0) 37 Insulins 3·30 4·45 34·8% (15·1, 54·5) 4·58 12·56 174·4% (113·9, 235·0) 38 Cardiac Therapy Agents 699·28 607·27 -13·2% (-26·9, 0·6) 908·12 825·49 -9·1% (-31·9, 13·1) 39 Lipid Regulating Agents 522·34 504·58 -3·4% (-19·9, 13·1) 781·97 1629·11 108·3% (59·8, 156·9) 40 Antihypertensives 3521·47 3418·79 -2·9% (-15·5, 9·7) 5200·86 6177·49 18·8% (-2·8, 40·3)** 41 Antineoplastics 35·38 34·21 -3·3% (-15·4, 8·7) 46·14 48·13 4·3% (-16·3, 24·9) 42 Cytostatic Hormones 29·48 30·58 3·7% (-10·1, 17·6) 39·82 47·52 19·3% (-5·1, 43·8) on September 26, 2021 by guest. Protected copyright. 43 Immunostimulating 0·65 0·43 -35·0% (-45·1, -25·0) 0·81 0·60 -26·3% (-45·0, -7·6) 44 Agents 45 *Bold9 signifies that the change is statistically significant (i.e., confidence interval does not include the null value of 0). **10 The absolute five-year difference, which is estimated using more precise method, is significant. See online appendix Table 43. 46 Formatted: Tab stops: 5.69", Left 11 47 12 48 13 49 14 50 15 51 16 Table 3. Immediate Impact of UCS on Hospital Sector Market Share* 52 53 54 55 21 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 53 of 58 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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7 8 9 Therapeutic Area Licensing Status Immediate post-policy 10 absolute change in % market share (95% CI) 11 DIABETES 12 Antidiabetics Originator brand -0·3% (-1·6, 1·0) 13 Branded generic -12·3% (-16·0, -8·7) 14 Generic -3·5% (-5·8, -1·1) 15 For GPO peer16·1% review (12·0, 20·2) only 16 Insulins*** Originator brand** -0·04% (-0·4, 0·3) 17 Branded generic 7·0% (2·9, 11·1) 18 Generic -6·2% (-10·3, -2·1) 19 CARDIOVASCULAR DISEASE 20 21 Antihypertensives Originator brand** -0·1% (-2·3, 2·0) 22 Branded generic** -0·2% (-6·1, 1·8) 23 Generic -5·7% (-8·3, -3·0) 24 GPO 5·3% (-0·1, 10·6) 25 Lipid Regulating Originator brand** -7·8% (-10·2, -5·4) 26 Agents 27 Branded generic** 7·6% (5·1, 10·0) Generic 0·2% (-0·4, 0·7) 28 GPO 0·2% (-0·3, 0·8) 29 Cardiac Therapy Originator brand 0·1% (-0·8, 1·0) 30 Branded generic** -13·5% (-20·5, -6·5) 31 Generic -4·3% (-6·2, -2·4) 32 GPO 21·6% (15·0, 28·1) 33 CANCER***

34 http://bmjopen.bmj.com/ Antineoplastics Originator brand 1·1% (-1·0, 3·2) 35 Branded generic -1·0% (-5·4, 3·4) 36 Generic 0·4% (-2·7, 3·4) 37 Cytostatic Hormones Originator brand** 0·4% (-5·4, 6·1) 38 Branded generic** -7·7% (-12·0, -3·5) 39 Generic** 6·0% (1·4, 10·6) 40 Immunostimulating Originator brand -6·4% (-9·7, -3·0) 41 Agents 42 Branded generic 4·5% (1·7, 7·3) on September 26, 2021 by guest. Protected copyright. 43 Generic -0·2% (-0·3, 0·02) 44 1 *Bold signifies a statistically significant regression coefficient (p<0.05). Changes are in absolute terms (i.e., percentage point change). 2 **Quadratic model (which has a squared post-policy term) fits better than linear model. 45 3 ***GPO did not produce any insulins or cancer medicines during the study period. 46 4 Note 1: See online appendix Table 54 and Figures 9-16 for market share regression coefficients and figures for all therapeutic areas 5 Note 2: Aside from the immediate level changes following the policy, there were few major changes in market share. See online appendix, Table 47 6 65 for absolute one- and five-year differences. 48 7 49 8 50 9 51 10 52 11 Figure Index (attached in separate document):* 53 54 55 22 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 54 of 58 BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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7 8 9 1 Figure 1. Standard Units Per Capita by Quarter: Insulin (Hospital vs. Retail) 10 2 11 3 Figure 2. Standard Units Per Capita by Quarter: Antihypertensives (Hospital vs. Retail) 12 4 13 5 Figure 3. Licensing Status Market Share by Quarter: Antidiabetics (Hospital Sector) 14 6 15 7 Figure 4. Licensing Status Market Share by Quarter: Cardiac Therapy Products (Hospital 8 Sector) For peer review only 16 9 17 10 *The grey box in each figure represents the 3-quarter UCS roll-out period. 18 11 19 12 Online appendix (attached in separate document) 20 13 21 14 22 23 24 25 26 27 28 29 30 31 32 33

34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on September 26, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 23 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 55 of 58 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2012-001686 on 28 November 2012. Downloaded from

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34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on September 26, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml