Drugs - Real World Outcomes (2018) 5:109–116 https://doi.org/10.1007/s40801-018-0133-1 ORIGINAL RESEARCH ARTICLE Use of Topical Tacrolimus and Topical Pimecrolimus in Four European Countries: A Multicentre Database Cohort Study 1 1,8 2 • • • Josephina G. Kuiper Myrthe P. P. van Herk-Sukel Jordi Castellsague 3 4 5 2 • • • • Anton Pottega˚rd Ingega¨rd Anveden Berglind Daniel Dedman Lia Gutierrez 6 3 4 5 • • • • Brian Calingaert Jesper Hallas Anders Sundstro¨m Arlene M. Gallagher 6 7 6 2 • • • James A. Kaye Carolina Pardo Kenneth J. Rothman Susana Perez-Gutthann Published online: 7 May 2018 The Author(s) 2018 Abstract database in Sweden (2006) through 2011. Use was assessed Background Despite the concerns about a potential separately for children (B 18 years) and adults. increased risk of skin cancer and lymphoma with the use of Results 32,052 children and 104,902 adults were treated topical tacrolimus and pimecrolimus, no population-based with topical tacrolimus, and 32,125 children and 58,280 studies have given an overview of the use of these drugs in adults were treated with topical pimecrolimus. The number Europe. of users increased rapidly after ﬁrst availability, especially Objective To assess the use of topical tacrolimus and for topical tacrolimus. Topical tacrolimus was more fre- pimecrolimus in children and adults in Europe. quently used in all countries except Denmark. For both Methods Multicentre database cohort study comprising drugs, there was a decrease in users after 2004 in the data from the Netherlands, Denmark, Sweden and the UK. Netherlands and Denmark and after 2005 in the UK, We analysed users of topical tacrolimus and pimecrolimus especially among children. This decrease was largest in starting from the date of ﬁrst availability (between 2002 Denmark. The decrease in the number of users was tem- and 2003) or start establishment of the prescription porary for topical tacrolimus, while use remained relatively low for topical pimecrolimus. Conclusions The number of topical tacrolimus and pime- & Josephina G. Kuiper crolimus users increased rapidly after regulatory approval. A email@example.com transient reduction in topical tacrolimus use and a persistent PHARMO Institute for Drug Outcomes Research, Van reduction in topical pimecrolimus use was seen after 2004 in Deventerlaan 30-40, 3528 AE Utrecht, The Netherlands the Netherlands and Denmark and after 2005 in the UK. Epidemiology, RTI Health Solutions, Av. Diagonal, 605, 9-1, 08028 Barcelona, Spain Department of Public Health, University of Southern Key Points Denmark, J.B. Winsløws Vej 9B, 5000 Odense, Denmark Unit of Clinical Epidemiology, Department of Medicine, This multidatabase cohort study assessed the use of Centre for Pharmacoepidemiology, Karolinska Institutet, Solnava¨gen 1, 171 77 Stockholm, Sweden topical tacrolimus and topical pimecrolimus in children and adults in Europe. Clinical Practice Research Datalink, Medicines and Healthcare products Regulatory Agency, 151 Buckingham The number of users of topical tacrolimus and Palace Road, Victoria, London SW1W 9SZ, UK topical pimecrolimus increased rapidly after Epidemiology, RTI Health Solutions, Research Triangle regulatory approval. Park, 3040 Cornwallis Road, Research Triangle Park, NC 27709-2194, USA A transient reduction in topical tacrolimus use and a Pharmacovigilance Department, Astellas Pharma Europe, persistent reduction in topical pimecrolimus use was Sylviusweg 62, 2333 BE Leiden, The Netherlands seen after 2004 in the Netherlands and Denmark and University Medical Center Utrecht, Heidelberglaan 100, after 2005 in the UK. 3584 CX Utrecht, The Netherlands 110 J. G. Kuiper et al. 1 Introduction European countries: the PHARMO Database Network (PHARMO) in the Netherlands, the Danish National Pre- Atopic dermatitis (AD) is a chronic inﬂammatory skin scription Registry, the Swedish Prescribed Drug Registry, and the Clinical Practice Research Datalink (CPRD) in the disease with a wide range of clinical presentations and is one of the most common skin disorders in children [2, 3]. UK. The PHARMO Database Network is a population-based, For many years, the most common treatment for AD was topical corticosteroids. In 2002, new topical treatment patient-centric data tracking system that includes detailed information on prescribed healthcare products dispensed by options in the form of tacrolimus ointment and pime- crolimus cream were approved for the treatment of AD. the outpatient pharmacies [9, 10]. The PHARMO Database Network covers a catchment area representing more than 4 Topical tacrolimus and topical pimecrolimus are the only million residents. In Denmark and Sweden, each national topical calcineurin inhibitors (TCIs) in Europe. In 2002, topical tacrolimus was approved for short or intermittent healthcare system provides universal coverage to all resi- dents. The Danish National Prescription Registry started in long-term treatment of moderate to severe AD in Europe. Two concentrations of topical tacrolimus are available; 1995 and contains data on prescribed and dispensed med- icine for all 5.7 million residents in Denmark . The 0.1% for use in patients over 16 years of age, and 0.03% for use in children over 2 years of age. The indication for Swedish Prescribed Drug Registry started in July 2005 and contains data on prescribed and dispensed medicine for all topical tacrolimus was extended in 2009 to maintenance treatment of AD. Topical pimecrolimus in a concentration 9.2 million residents in Sweden . The CPRD contains data collated by General Practitioners (GPs) for over 5 of 1% was approved in 2002 for the treatment of mild-to- million active patients representing over 8% of the general moderate AD in patients over 2 years of age. Both drugs population and includes detailed information on prescrip- are approved for second-line treatment only, for patients in tions issued in primary care . Drug dispensings and whom other treatments have been ineffective or are contraindicated. prescriptions are coded according to the WHO Anatomical Therapeutic Chemical (ATC) Classiﬁcation System in At the time of approval of both products, the long-term safety in humans was not fully established, though animal PHARMO (Netherlands), Denmark and Sweden, and according to Gemscript codes in CPRD (UK). studies indicated a potential risk of skin cancer of both products [4, 5]. In March 2005, the US Food and Admin- Hereafter, issued prescriptions recorded in CPRD are referred to as dispensings. istration (FDA) issued a public health advisory followed by a label change in January 2006, including a boxed warning 2.2 Participants [6, 7]. Similarly, the European Medicines Agency’s Com- mittee for Medicinal Products for Human Use (CHMP) The study population in each country comprised children recommended a change in the product information and a (B 18 years) and adults ([18 years) with a dispensing of Direct Healthcare Professional Communication (DHPC) letter was sent by the marketing authorization holders of topical tacrolimus or topical pimecrolimus between 2002 and 2011. The start of the study period differed across topical tacrolimus and topical pimecrolimus to healthcare professionals with important risk minimization measures countries, depending on the launch date of topical tacroli- mus and topical pimecrolimus in each country, and in . To date, no population-based studies have given an Sweden on the establishment of the prescription database in 2005. Topical tacrolimus was available from 2002 in all overview of the use of topical tacrolimus and topical pimecrolimus for the treatment of AD in Europe. There- countries, and topical pimecrolimus from 2002 in Denmark and from 2003 in the other countries. fore, the purpose of this population-based study is to give an overview of the use of topical tacrolimus and topical 2.3 Treatment Characteristics pimecrolimus across population-based health databases in four European countries between 2002 and 2011. In the study period, the mean total number of dispensings per patient of topical tacrolimus and topical pimecrolimus 2 Methods was calculated. The number of users of topical tacrolimus and topical pimecrolimus by year was also determined. For 2.1 Study Design and Setting each country, the proportion of total topical tacrolimus and topical pimecrolimus users was tabulated by year. The In this multicentre database cohort study, data were proportion of users in each year was calculated by dividing the number of topical tacrolimus users or topical pime- retrieved from population-based health databases in four crolimus users in a speciﬁc year by the total number of Tacrolimus and Pimecrolimus Use in Four European Countries 111 topical tacrolimus users or topical pimecrolimus users of topical pimecrolimus dispensings ranged from 2.0 throughout the study period. The strength (0.1 or 0.03%) of (Netherlands) to 2.4 (UK) among children and from 2.0 the ﬁrst topical tacrolimus dispensing was determined. The (Sweden) to 2.9 (UK) among adults. ﬁrst switch between topical tacrolimus and topical pime- In Sweden, the prescription registry started in July 2005 crolimus (or vice versa) that occurred between the ﬁrst and users from January 2006 and onwards were included. dispensing in the study period and the end of that patient’s Information in the ﬁrst 4 years after launch of topical follow-up was reported. tacrolimus and topical pimecrolimus was therefore not available on an individual level. However, based on 2.4 Statistical Analyses aggregate Swedish sales data on prescription of the drugs during the entire period of marketing (data not shown), a The data extraction and analysis for each database were sharp decline in sales of topical tacrolimus was observed based on a common protocol. Treatment characteristics between 2004 and 2006 and a minor decline of topical were reported as percentages for categorical variables, and pimecrolimus between 2004 and 2005. Across the other mean with standard deviation (SD) (if available) for con- data sources, the number of topical tacrolimus users tinuous variables. All analyses were conducted within two increased steadily after launch among both children and age cohorts (B18 years and [18 years) and within each adults (Table 2). For topical pimecrolimus, there was a data source. peak in the number of users in the ﬁrst 2 years after its ﬁrst availability, especially among children (Fig. 1). For topical tacrolimus, there was a decrease in users seen after 2004 in 3 Results the Netherlands and Denmark, and after 2005 in the UK, especially among children. In the Netherlands, the year In total, there were 32,052 children and 104,902 adults 2004 contributed 16% of the total number of children using treated with topical tacrolimus, and 32,125 children and topical tacrolimus and declined to 13% in the year 2005. In 58,280 adults treated with topical pimecrolimus. In Den- Denmark, the year 2004 contributed 14% of the total mark the most commonly used TCI for both children and number of children using topical tacrolimus in Denmark adults was topical pimecrolimus, whereas topical tacroli- and also declined to 13% in the year 2005. In the UK, the mus was the predominant TCI choice for both age groups year 2005 contributed 22% of the total number of children in the other countries. Of the study population, the most using topical tacrolimus in the UK and declined to 18% in users of topical pimecrolimus were from Denmark (74% of the year 2006. For topical pimecrolimus, a decline in the all children and 69% of all adults) (Table 1). Denmark and number of users of topical pimecrolimus was seen after Sweden contributed together 71% of all children and 70% 2004 for children and after 2005 for adults in the Nether- of all adult users of topical tacrolimus. The mean number lands. This was seen after 2004 in Denmark and after 2005 of topical tacrolimus dispensings per child varied between in the UK for both children and adults. After 2007, there 2.0 (Sweden) and 4.6 (UK). For adults, this ranged from was a difference seen in the number of users between 2.2 (Denmark and Sweden) to 3.6 (UK). The mean number topical tacrolimus and topical pimecrolimus. In 2011, the Table 1 Topical tacrolimus and topical pimecrolimus use, stratiﬁed by country Topical tacrolimus cohort Topical pimecrolimus cohort Children Mean number Adults Mean number Children Mean number Adults Mean number (B 18 years) of ([18 years) of (B 18 years) of ([18 years) of (N = 32,052) prescriptions (N = 104,902) prescriptions (N = 32,125) prescriptions (N = 58,280) prescriptions n (%) per user n (%) per user n (%) per user n (%) per user PPHARMO 5037 (16) 2.7 19,264 (18) 2.7 3452 (11) 2.1 8,072 (14) 2.2 (NL) Denmark 12,976 (40) 2.5 35,112 (33) 2.2 23,921 (74) 2.3 40,013 (69) 2.3 Sweden 10,026 (31) 2.0 39,294 (37) 2.2 1623 (5) 2.0 4766 (8) 2.0 CPRD (UK) 4013 (13) 4.6 11,232 (11) 3.6 3129 (10) 2.4 5429 (9) 2.9 NL Netherlands, CPRD Clinical Practice Research Datalink, UK United Kingdom In Sweden, data from July 2005 were available, but only users from 2006 were included 112 J. G. Kuiper et al. Table 2 The number of users of topical tacrolimus and topical pimecrolimus by year, stratiﬁed by country 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 Topical tacrolimus cohort Children (B 18 years) PHARMO (NL) 55 701 782 650 571 763 823 1020 1018 1049 Denmark 550 1270 1876 1733 1424 680 1877 2816 3294 3486 Sweden –––– 1423 1566 2070 2482 2959 3041 CPRD (UK) 302 639 784 902 734 662 655 800 828 920 Adults ([ 18 years) PHARMO (NL) 97 2396 3399 3155 2620 2742 2853 3531 3984 4347 Denmark 1172 2845 4097 3819 3406 2955 5348 7813 9231 10,532 Sweden –––– 5054 6305 7983 10,181 12,144 13,396 CPRD (UK) 498 1251 1640 1983 1892 1926 1946 2271 2398 2543 Topical pimecrolimus cohort Children (B 18 years) PHARMO (NL) – 387 1108 720 453 523 494 452 360 329 Denmark 2282 5352 6015 4909 3542 1827 2866 2928 3088 2842 Sweden –––– 465 398 376 346 300 265 CPRD (UK) – 488 811 869 601 396 368 374 346 350 Adults ([ 18 years) PHARMO (NL) – 424 1272 1650 1152 1337 1204 1360 1295 1454 Denmark 1996 5667 7346 6649 6081 4610 5797 7067 7568 7984 Sweden –––1 1077 1028 1012 1123 1208 1099 CPRD (UK) – 596 970 1170 969 751 737 835 794 776 NL Netherlands, CPRD Clinical Practice Research Datalink, UK United Kingdom In Sweden, data from July 2005 were available, but only users from 2006 were included number of topical tacrolimus users had increased to a level ranged from 10% in the Netherlands and the UK to 13% in above that of 2004/2005, for both children and adults and Sweden. Similar results were found for adults (Table 3). in all countries. For topical pimecrolimus, the number of users remained relatively unchanged except in Sweden, where the decrease in the number of children using topical 4 Discussion pimecrolimus continued through 2011. In Denmark, the majority of children received topical This is the ﬁrst study evaluating the use of topical tacro- tacrolimus with a strength of 0.1% (61%) (Fig. 2) whereas limus and topical pimecrolimus across four European a strength of 0.03% was predominantly dispensed to chil- countries in both children and adults. The results of this dren (56–69%) in all other countries. Adults were more population-based multicentre database cohort study pro- often dispensed a topical tacrolimus strength of 0.1% in all vide an overview of the use of topical tacrolimus and countries (66–88%). In the UK, a small number of patients topical pimecrolimus in four European countries. (67 children and 260 adults) had dispensings for both In this study, there was a difference seen in the type of topical tacrolimus strengths (0.03 and 0.1%) on the same TCI prescribed to children and adults across the four day; these patients contributed to both groups in Fig. 2. countries; in Denmark most children and adults were pre- Overall, the number of users switching from initially scribed topical pimecrolimus, whereas in the other coun- prescribed topical pimecrolimus to topical tacrolimus was tries the preference was for topical tacrolimus. The use of higher compared with users starting with topical tacrolimus topical tacrolimus and topical pimecrolimus increased in and switching to topical pimecrolimus (Table 3). The the ﬁrst years after approval. This increase was steeper for number of children switching from topical tacrolimus to topical pimecrolimus. There was a decrease seen in topical topical pimecrolimus during follow-up ranged from 1% in tacrolimus and topical pimecrolimus users in the Nether- Sweden to 7% in Denmark. The number of children lands and Denmark from 2004 and in the UK from 2005. switching from topical pimecrolimus to topical tacrolimus The number of users of topical tacrolimus increased again Tacrolimus and Pimecrolimus Use in Four European Countries 113 35% 35% 30% 30% 25% 25% 20% 20% PHARMO (NL) PHARMO (NL) 15% Denmark 15% Denmark Sweden* 10% Sweden* 10% CPRD (UK) CPRD (UK) 5% 5% 0% 0% Years Years C D 35% 35% 30% 30% 25% 25% 20% PHARMO (NL) 20% PHARMO (NL) 15% Denmark 15% Denmark 10% Sweden* Sweden* 10% CPRD (UK) 5% CPRD (UK) 5% 0% 0% Years Years Fig. 1 Proportion of total users in each country over the years among pimecrolimus, stratiﬁed by country. *In Sweden, data from July 2005 a children using topical tacrolimus, b adults using topical tacrolimus, were available, but only users from 2006 were included c children using topical pimecrolimus and d adults using topical from 2007 onwards, while the number of users of topical . Following the extension of the indication of topical pimecrolimus remained unchanged. For Sweden, data on tacrolimus to maintanance treatment of AD in the EU in an individual level were only available from 2006 and 2009, a further reminder about minimization of cancer risk onwards. However, based on aggregate Swedish sales was sent to all healthcare providers . However, this similar results were found compared to the other countries. reminder seems to have less impact on the number of users The pattern of use of topical tacrolimus and topical of both topical tacrolimus and topical pimecrolimus. pimecrolimus may have been the result of the increased The change in the pattern of use following these regu- awareness of the concerns about a potential increased risk latory actions and responses from the the medical com- of skin cancer and lymphoma with the use of topical munity was also seen based on worldwide sales data of tacrolimus and topical pimecrolimus [14, 15], but there is topical tacrolimus and topical pimecrolimus published by no additional evidence to support this explanation. How- Siegfried et al. . Here, worldwide sales data of topical ever, regulatory measures were undertaken, including a tacrolimus and topical pimecrolimus showed a decrease in public health advisory in March 2005 and a label change in sales within a year of the public health advisory and January 2006 [6, 7]. In the European Union as well as the updated labelling. Comparable with the results in our USA the labelling of topical tacrolimus and topical pime- study, the wordwide sales of topical pimecrolimus con- crolimus was updated by adding a warning about cautious tinued to decline, while the sales of topical tacrolimus use of topical tacrolimus and topical pimecrolimus in order slightly increased. to reduce the potential risk of skin cancer and lymphoma. Topical tacrolimus and topical pimecrolimus are not In addition, a DHPC letter was sent by the marketing indicated for children younger than 2 years of age. How- authorization holders of topical tacrolimus and topical ever, in our study, we know that off-label use of topical pimecrolimus to healthcare professionals with important tacrolimus in children younger than 2 years of age did risk minimization measures, in accordance with the CHMP occur and ranged from 0.3% in the Netherlands to 3.7% in Proporon of total users in 2002-2011 Proporon of total users in 2002-2011 Proporon of total users in 2002-2011 Proporon of total users in 2002-2011 2011 114 J. G. Kuiper et al. 100% 90% 80% 69% PHARMO (NL) 70% (N = 4,764) 61% 59% 56% 60% Denmark (N = 10,571) 50% 44% 41% 39% Sweden 40% 33% (N = 9,845) 30% CPRD (UK) 20% (N = 3,714) 10% 0% 0.03% 0.1% NL = Netherlands; CPRD = Clinical Pracce Research Datalink; UK = United Kingdom; Note: In CPRD, 67 children and 260 adults had a dispensing for both a tacrolimus strength of 0.03% and 0.1% on the same day and contributed to both groups. 100% 88% 86% 90% 81% 80% PHARMO (NL) 68% 70% (N = 18,184) 60% Denmark (N = 30,646) 50% Sweden 40% 34% (N = 38,349) 30% 19% CPRD (UK) 20% 14% 12% (N = 10,556) 10% 0% 0.03% 0.1% NL = Netherlands; CPRD = Clinical Pracce Research Datalink; UK = United Kingdom Fig. 2 Strength of ﬁrst topical tacrolimus prescription among a chil- and 0.1% on the same day and contributed to both groups. NL dren and b adults, stratiﬁed by country. Note In CPRD, 67 children Netherlands, CPRD Clinical Practice Research Datalink, UK United and 260 adults had a dispensing for tacrolimus strengths of both 0.03 Kingdom Denmark and for topical pimecrolimus from 1.4% in the from GP prescriptions, which do not contain information Netherlands to 11% in Denmark (data not shown). A pre- on whether the prescription was actually ﬁlled or not. For vious study also showed that off-label use of topical Denmark and Sweden, information on topical tacrolimus tacrolimus and topical pimecrolimus in children younger and topical pimecrolimus dispensings was obtained from than 2 years of age decreased substantially in association national registers covering the entire Danish and Swedish with regulatory actions . population. In Sweden, full data on the number of users In this large population-based study in European data- was available from 2006 onwards and the pattern of use on bases, the data extraction and analysis for each health an invididual level could only be determined after that database were based on a common protocol that permitted period. Data from the Netherlands and the UK were combining the results across databases. However, some available for a subset of the population, but have been differences between the databases exist. In the UK, data on shown to be representative of the general population of topical tacrolimus and topical pimecrolimus were obtained these countries [13, 19–21]. Percent of total users Percent of total users Tacrolimus and Pimecrolimus Use in Four European Countries 115 Table 3 Switching patterns from ﬁrst prescription of topical tacrolimus and topical pimecrolimus during follow-up, stratiﬁed by country Topical tacrolimus cohort Topical pimecrolimus cohort PHARMO Denmark Sweden CPRD PHARMO Denmark Sweden CPRD (NL) (UK) (NL) (UK) Children (B 18 years) Number of users 4764 10,571 9845 3714 3188 23,324 1502 2869 Number of switchers during follow- 307 (6) 693 (7) 124 (1) 241 (6) 311 (10) 2649 197 (13) 277 (10) up , n (%) (11) Months between index date and ﬁrst 15.1 (17.8) 23.6 15.3 20.2 20.8 (9.0) 26.5 22.2 19.6 switch, mean (SD) (25.9) (13.9) (20.7) (27.8) (16.9) (20.8) Number of switchers during 264 (6) 597 (6) 114 (1) 227 (6) 273 (9) 2405 174 (12) 266 (9) childhood, n (%) (10) Months between index date and ﬁrst 18.8 (21.1) 18.9 14.1 18.6 22.9 (23.9) 23.9 20.7 18.5 switch, mean (SD) (22.5) (13.1) (19.2) (26.5) (15.9) (19.6) Adults ([18 years) Number of users 18,184 30,646 38,349 10,556 7028 37,566 4148 4837 Number of switchers during follow- 909 (5) 1683 (6) 523 (1) 447 (4) 680 (10) 3743 468 (11) 427 (9) up , n (%) (10) Months between index date and ﬁrst 18.2 (19.2) 23.2 16.1 19.5 16.3 (20.0) 26.7 21.5 16.7 switch, mean (SD) (25.6) (15.1) (21.1) (27.5) (19.0) (19.3) NL Netherlands, CPRD Clinical Practice Research Datalink, UK United Kingdom, SD standard deviation Based on ﬁrst prescription Follow-up continues into adulthood when data are available They have participated in studies funded by pharmaceutical compa- 5 Conclusion nies (Alcon, Almirall, Astellas, Astra-Zeneca, Boehringer-Ingelheim, Servier and Leo Pharma), all with funds paid to the institution where In conclusion, the use of topical tacrolimus and topical they were employed (no personal fees) and with no relation to the pimecrolimus grew rapidly after regulatory approval. work reported in this paper. Daniel Dedman and Arlene Gallagher are employees of the Clinical Practice Research Datalink (CPRD), which Safety warnings issued by regulatory agencies about a provides contract research services for government and related potential risk of cancer may have contributed to the tem- healthcare authorities, and pharmaceutical companies. Ingega¨rd porary reduction in users of topical tacrolimus and persis- Anveden Berglind and Anders Sundstro¨m were both full-time tent reduction in users of topical pimecrolimus in all employees of the Centre for Pharmacoepidemiology at the Karolinska Institutet during the conduct of the study. They have both taken part countries, especially in children. in studies undertaken at the Centre, ﬁnanced by pharmaceutical companies, but have never received compensation personally from Acknowledgements The authors would like to thank the general any company. Carolina Pardo is an employee of Astellas Pharma practitioners for contributing information to the Clinical Practice Europe. Research Datalink (CPRD) in the UK and the healthcare providers for contributing information to the PHARMO Database Network. The Funding The study was funded by Astellas Pharma. In June 2016, research team chose the acronym JOELLE to honor of Dr. Joelle LEO Pharma became the marketing authorization holder of Pro- Erkens, pharmacoepidemiologist at Astellas and formerly at topic and provided partial funding. The contract grants the research PHARMO Institute, who was lost to the research team in June 2011 team independent publication rights. The sponsor had no role in the upon her untimely death. data collection or analysis and was not involved in the interpretation of results; however, in line with the ENCePP Guide on Method- Disclosures Josephina G. Kuiper and Myrthe P.P. van Herk-Sukel ological Standards in Pharmacoepidemiology , the sponsor had the are employees of the PHARMO Institute for Drug Outcomes opportunity to view the results and interpretations included in the Research. This independent research institute performs ﬁnancially manuscript and provide comments before submission of the manu- supported studies for government and related healthcare authorities script for publication. and several pharmaceutical companies. Jordi Castellsague (retired), Lia Gutierrez, Brian Calingaert, Kenneth J. Rothman, James A. Kaye Data Availability All authors had full access to all the data in the and Susana Perez-Gutthann are full-time employees of RTI Health study and all take responsibility for the integrity of the data and the Solutions, an independent nonproﬁt research organization that does accuracy of the data analysis. The datasets generated during and/or work for government agencies and pharmaceutical companies. As analysed during the current study are not publicly available for pri- employees of RTI Health Solutions, Susana Perez-Gutthann, Kenneth vacy reasons. J. Rothman, and James A. Kaye, also participate in scientiﬁc advisory boards (for studies and medications) that are funded by pharmaceu- Open Access This article is distributed under the terms of the tical companies. Jesper Hallas and Anton Pottega˚rd are employees of Creative Commons Attribution-NonCommercial 4.0 International the Department of Public Health, University of Southern Denmark. 116 J. G. Kuiper et al. License (http://creativecommons.org/licenses/by-nc/4.0/), which per- 10. van Herk-Sukel MP, van de Poll-Franse LV, Lemmens VE, mits any noncommercial use, distribution, and reproduction in any Vreugdenhil G, Pruijt JF, Coebergh JW, Herings RM. 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Drugs - Real World Outcomes – Springer Journals
Published: May 7, 2018
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