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BMJ Open Is Committed to Open Peer Review. As Part of This Commitment We Make the Peer Review History of Every Article We Publish Publicly Available BMJ Open is committed to open peer review. As part of this commitment we make the peer review history of every article we publish publicly available. When an article is published we post the peer reviewers’ comments and the authors’ responses online. We also post the versions of the paper that were used during peer review. These are the versions that the peer review comments apply to. The versions of the paper that follow are the versions that were submitted during the peer review process. They are not the versions of record or the final published versions. They should not be cited or distributed as the published version of this manuscript. BMJ Open is an open access journal and the full, final, typeset and author-corrected version of record of the manuscript is available on our site with no access controls, subscription charges or pay-per-view fees (http://bmjopen.bmj.com). If you have any questions on BMJ Open’s open peer review process please email [email protected] BMJ Open Pediatric drug utilization in the Western Pacific region: Australia, Japan, South Korea, Hong Kong and Taiwan Journal: BMJ Open ManuscriptFor ID peerbmjopen-2019-032426 review only Article Type: Research Date Submitted by the 27-Jun-2019 Author: Complete List of Authors: Brauer, Ruth; University College London, Research Department of Practice and Policy, School of Pharmacy Wong, Ian; University College London, Research Department of Practice and Policy, School of Pharmacy; University of Hong Kong, Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy Man, Kenneth; University College London, Research Department of Practice and Policy, School of Pharmacy; University of Hong Kong, Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy Pratt, Nicole; University of South Australia, Sansom Institute for Health Resarch Park, Rea Woong; Ajou University Cho, Soo-Yeon; Ajou University Li, Yu-Chuan (Jack); Taiwan Medical University, College of Medical Science and Technology Iqbal, Usman; Taipei Medical University, Graduate Institute of Biomedical Informatics, College of Medical Science and Technology Nguyen, Phung-Anh; National Yang Ming University, Institute of Biomedical Informatics Schuemie, Martijn; Janssen Research and Development, Epidemiology Analytics; University of California, Los Angeles, Department of Biostatistics Keywords: CLINICAL PHARMACOLOGY, EPIDEMIOLOGY, PAEDIATRICS For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 70 BMJ Open 1 2 3 Pediatric drug utilization in the Western Pacific region: Australia, Japan, South Korea, Hong Kong and 4 5 6 Taiwan 7 8 a a,b b c 9 Authors: Ruth Brauer , PhD, Ian C.K. Wong , PhD, Kenneth Man , MPH, Nicole Pratt , PhD, 10 11 Rae Woong Parkd, MD, PhD, Soo-Yeon Chod, RN, MPH, Li, Yu-Chuan (Jack) Lie, MD, PhD, 12 13 Usman Iqbale, PhD, Alex Nguyene, PhD, Martijn Schuemief, PhD. 14 15 16 For peer review only 17 18 Affiliations: aUCL School of Pharmacy, London, United Kingdom; bUniversity of Hong Kong, Hong Kong; 19 20 c d 21 University of South Australia, Adelaide, Australia; Ajou University School of Medicine, Suwon, South- 22 23 Korea; eTaipei Medical University, Taipei, Taiwan; and fJanssen Research and Development, New Jersey. 24 25 26 27 Corresponding author: Martijn Schuemie ([email protected]) 28 29 30 31 32 Funding Source: No funding was secured for this study. 33 34 35 Word count: 2887 36 37 38 39 40 41 42 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 BMJ Open Page 2 of 70 1 2 3 Abstract 4 5 6 Objective: To measure the pediatric user and prescription prevalence in inpatient and ambulatory 7 8 settings in South Korea, Hong Kong, Taiwan, Japan and Australia by age and gender. A further objective 9 was to list the most commonly used drugs per drug class, per country. 10 11 12 Design and setting: Hospital inpatient and insurance paediatric health care data from the following 13 14 databases were used to conduct this descriptive drug utilization study: (i) the South Korean Ajou 15 16 University School of MedicineFor (AUSOM)peer database; review (ii) the Hong Kong only Clinical Data Analysis and 17 Reporting System (CDARS); (iii) the Japan Medical Data Center (JMDC); (iv) Taiwan’s National Health 18 19 Insurance Research Database (NHIRD); and (v) the Australian Pharmaceutical Benefits Scheme (PBS). 20 21 Country specific data were transformed into the Observational Medical Outcomes Partnership (OMOP) 22 Common Data Model (CDM). 23 24 25 Patients: Follow-up of children with at least 1 day of observation in any of the respective databases 26 27 started in January 2009 and ended in December 2013. 28 29 30 Main outcome measures: For each drug class we assessed the per-protocol overall user and 31 prescription prevalence rates (per 1000 persons) per country and setting. 32 33 34 Results: Our dynamic study cohort comprised 1,574,524 children (52.9% male). The highest proportion 35 36 of dispensings was recorded in the youngest age category (<2 years) for inpatients (45.1%) with a 37 38 relatively high user prevalence of analgesics and antibiotics. Adrenergics, antihistamines, mucolytics and 39 corticosteroids were used in 10-15% of patients. For ambulatory patients, the highest proportion of 40 41 dispensings was recorded in the middle age category (2-11 years, 67.1%) with antibiotics the most 42 43 dispensed drug overall. 44 45 46 Conclusions: Important differences in drug pediatric utilization patterns were identified between four 47 East-Asian countries and Australia. The widespread east-Asian use of mucolytics warrants further 48 49 investigation. 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 70 BMJ Open 1 2 3 Strengths and limitations of this study 4 5 6 7 We conducted the largest Western pacific pediatric drug utiIisation study to date using a 8 9 common data model (CDM) which allowed us to rank the user and prescription prevalence of 10 11 fifteen different drug classes in South Korea, Hong Kong, Taiwan, Japan and Australia. 12 13 Our comprehensive overview of country-specific pharmacological agents used in both an 14 15 16 ambulatory andFor inpatient peer setting, by genderreview and age, included only data of 1,574,524 children and 17 18 identified important differences in drug pediatric utilization patterns. 19 20 Despite the differences in databases in terms of setting and study populations, we believe our 21 22 overview of prescription patterns and rankings is an important step to further investigate and 23 24 25 facilitate the rational use of drugs in pediatric populations in East Asia and Australia. 26 27 Over the counter (OTC) prescribing in individual countries was not captured and we may have 28 29 underestimated the true drug utilization of agents, such as paracetamol and some 30 31 antihistamines. 32 33 34 We collected data until the end of 2013 and acknowledge that, due to the rapid change in 35 36 pediatric licensing of therapeutic agents, some of our findings might be worthwhile replicating 37 38 with more current data. 39 40 41 42 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 BMJ Open Page 4 of 70 1 2 3 Introduction 4 5 6 In the absence of large randomised controlled trials (RCTs), observational data in the form of electronic 7 8 health records and insurance claims data have been used successfully to investigate both medication 9 10 errors and adverse drug events through retrospective analysis of drug exposure in children[1 2]. 11 12 Pediatric drug utilization data from East Asian countries are currently lacking. 13 14 15 A network of observational healthcare databases in South Korea, Hong Kong, Taiwan, Japan and 16 For peer review only 17 18 Australia was used to measure and compare the prevalence of drug prescribing in East Asian and 19 20 Australian children. Country specific data were transformed into the Observational Medical Outcomes 21 22 Partnership (OMOP) Common Data Model (CDM). Our primary aim was to measure the pediatric user 23 24 and prescription prevalence in inpatient and ambulatory settings in the five aforementioned countries 25 26 by age and gender. A further objective was to list the most commonly used drugs per drug class, per 27 28 29 country, in both an inpatient and ambulatory setting. 30 31 32 Methods 33 34 35 Data sources 36 37 38 We conducted a drug utilisation study using pediatric patient populations from the following databases: 39 40 (i) Ajou University School of Medicine (AUSOM) from South Korea; (ii) the Hong Kong Clinical Data 41 42 Analysis and Reporting System (CDARS); (iii) the Japan Medical Data Center (JMDC); (iv) Taiwan’s 43 44 45 National Health Insurance Research Database (NHIRD); and (v) the Australian Pharmaceutical Benefits 46 47 Scheme (PBS). All data were anonymized to protect patient confidentiality. 48 49 50 The South Korean and Hong Kong databases, AUSOM and CDARS, collect and archive the electronic 51 52 health records (EHR) of hospital inpatients. Briefly, AUSOM is an EHR database of a Korean teaching 53 54 hospital with 1,096 patient beds and 23 operating rooms with data for over 2,073,120 individuals, 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 70 BMJ Open 1 2 3 collected since 1994. By contrast, CDARS contains the data from all public hospitals in Hong Kong and 4 5 6 their associated ambulatory and primary care clinics since 1995 [3-5].
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