126 Graduate School for Health Research SHARE Self evaluation 2003-2008

126 Graduate School for Health Research SHARE Self evaluation 2003-2008

127 Evidence-Based Medicine in Practice 5

128 Graduate School for Health Research SHARE Self evaluation 2003-2008 1 Object i ve s a n d re s e a rch area Evidence-Based Medicine in Practice (EBM-P) concerns research bridging the gap between evidence and clinical practice in health care. This is done by adding evidence from observational studies to the body of knowledge provided by RCTs. Evidence in medicine is mainly derived from randomized clinical trials (RCT). Specific groups (children, pregnant women and the elderly) are generally excluded in RCTs. Moreover, in daily practice, patients have multiple disorders, come from different social and economic situations, and do not always follow the health care professionals recommendations. Evidence on actual practice, therefore, should preferably be verified or obtained from population-based cohort studies, which form the core of the current research activities of the EBM program. Information on the economic impact of changes and innovations in health care provide the necessary input on the feasibility of uptake of these changes in actual health care. Finally, findings on important improvements in health care often find their way too slowly to actual practice because of barriers in the organization of care, the health care provider or inadequate strategies for change. Implementation research adds this type of knowledge and forms the third pillar in bridging the gap between evidence and practice. The mission statement of the EBM-P research program is therefore to provide evidence for clinical practice based on epidemiological studies, economic evaluations and implementation research. A second mission of the program is to be the expertise center for support and improved methodology and quality of clinical research in the UMCG and related primary care settings (general practitioners and community pharmacists). Consultations and research facilities such as database development and data management are being provided for research. Up to 2005 our principal goal was to evaluate and understand primary care performance in terms of quality of care, to develop tools to support optimal care, and improve the implementation of scientific evidence in clinical practice with emphasis on pharmacotherapy. The program was evaluated as very good by the previous review committee, but there was concern about the sustainability. Inclusion of epidemiology, and health / pharmacoeconomics provides the necessary strengthening of the field. It brings together methodological expertise and theoretical knowledge important to advance evidence-based medicine in practice. Therefore the program was extended with three epidemiological groups in 2006. With this extension and the shift of the UMCG focus to healthy ageing, the focus of the program also shifted. Risk factors and predictors of age-related diseases became the major topics, together with their application in effective and cost-effective prevention. The emphasis is still on pharmacotherapy of multifactorial diseases (cardio-metabolic diseases / psychiatry / cancer), factors related to adverse pregnancy outcomes and the effectiveness of prevention measures (screening, vaccines). Pharmacotherapy is the most widely used treatment in clinical care, emphasizing the relevance of pharmacotherapy in everyday practice. The cohorts on which much of our research is based include both disease-based cohorts (notably diabetes), patient-based cohorts (notably pharmacy databases), and population-based cohorts (notably LifeLines).

Chapter 5 Evidence Based Medicine in Practice 129 The research areas of the program consist of three closely related themes: Epidemiology Pharmaceutical care Medical technology assessment (MTA) It is important to realize that these areas cross the borders of the four (initially five) departments participating in the program: Epidemiology (UMCG), Clinical Pharmacology (UMCG), Pharmaco-epidemiology & Pharmaco-economics (University of Groningen), Pharmacotherapy & Pharmaceutical Care (University of Groningen), and, previously, General Practice (UMCG). In line with the suggestions of the previous review committee, the program utilizes large-scale regional databases, either managed by researchers of the program or in close collaboration with other research groups (see facilities in section 5). The existing collaborative projects between the four departments form the basis for our policy to achieve a coherent multidisciplinary research program. To achieve this, the senior staff of the pertaining departments meet regularly to discuss and synchronize on the important calls for grant proposals. Secondly, we organize monthly research meetings where PhD students as well as senior staff present their work. This strategy has resulted both in improvements in running projects, as well as in new multidisciplinary research proposals. The structural collaboration with clinical groups has been extended, underlining the need for a multidisciplinary approach. The results of collaborative projects have a broader scope and thus will lead to faster implementation of evidence-based clinical practice. This is also achieved by active involvement in (Dutch) healthcare policy bodies, such as the CBG/ EMEA/ NHG (details listed in section 8). Likewise, the staff of the EBM-P program have been able to contribute to EBM in practice at a national level through positions or participation in several national programs (section 7).

130 Graduate School for Health Research SHARE Self evaluation 2003-2008 2 Composition of the re s e a rch program The EBM program has been extended since the last evaluation and now includes the departments of Epidemiology, Clinical Pharmacology, Pharmacoepidemiology & Pharmacoeconomics, as well as Pharmacotherapy. This strengthens the position and sustainability of the program and is in line with the recommendations of the peer review committee in 2003. Over the present evaluation period the Department of General Practice reduced its research activities in EBM, and is no longer part of the research program. The core staff of the program in 2008 consists of six professors and two associate professors The program is coordinated by two persons to assure continuity. Prof FM Haaijer-Ruskamp (Drug Utilization Studies) has been one of the coordinators since 2000, while Prof RP Stolk (Clinical Epidemiology) has been involved as a coordinator since 2006, when the program was extended. The other core staff members are: Prof LTW de Jong-van den Berg, professor of Pharmaco-epidemiology Prof MJ Postma, professor of Pharmaco-epidemiology Prof JRBJ Brouwers, professor of Pharmacotherapy Prof E Buskens, professor of Medical Technology Assessment Dr P Denig, associate professor of Drug Utilization Studies Dr GH de Bock, associate professor of Clinical Epidemiology Dr V Fidler, associate professor of Medical Statistics Table 1 provides a description of research staff. An explanation of the way research fte s are computed is given in chapter 1. Table 1 Research staff 2003 2004 2005 2006 2007 2008 fte n fte n fte n fte n fte n fte n Tenured staff Professor 1.40 4 1.30 5 1.00 4 1.73 7 2.29 7 2.36 7 Associate prof 0.08 2 0.68 2 1.29 5 1.25 4 1.26 4 Assistant prof 1.48 4 1.60 5 1.20 3 1.11 4 0.84 3 1.45 5 Total tenured 2.88 8 2.98 10 2.88 10 4.12 15 4.38 14 5.07 16 Non tenured staff Post doc 0.27 1 0.36 1 0.36 1 2.03 5 PhD 5.18 28 5.67 27 7.50 29 5.45 34 7.50 41 11.42 46 Total staff 8.06 36 8.65 37 10.65 40 9.93 50 12.24 56 18.52 67

Chapter 5 Evidence Based Medicine in Practice 131 Table 2 provides an overview of the various types of PhD students, as well as their progress. Table 2 PhDs, types and progress 2003 2004 2005 2006 2007 2008 n n n n n n Total 28 27 29 34 41 46 Type: AIO, MD/PhD 11 11 11 13 20 23 Bursary 4 4 6 7 7 8 Clinical Ext. funding 1 1 1 1 External 13 11 11 13 13 15 Progress: Graduated 5 8 4 4 5 4 In progress 22 19 25 30 34 42 Stopped 1 2 All groups within the program are active in applying for research grants in the area of evidencebased medicine. The main sources include the programs of the Netherlands Organisation for Health Research and Development (ZonMw) on Prevention and Effectiveness. Every year a number of proposals are submitted, and during the evaluation period a substantial number of grants were received (details are provided in section 6). The second source for funding of personnel to perform studies in evidence-based medicine in practice ranges from national research consortia such as TI Pharma and PREDICCt, charity funds (Collectebusfondsen) for specific diseases, like the Kidney Foundation, to public and private organizations in the healthcare field. In collaboration with clinically based researchers (including primary care) and other research programs within SHARE (for example ICPE), proposals are submitted and granted for translational projects, investigating how to apply the results from basic and epidemiological studies to daily clinical practice. The (limited) resources from the university directly provided for our program are used for PhD projects conducted by two or more groups within the EBM program. This is aimed at further strengthening the interaction between the participating groups. These funds are also used to enable the initial development of innovative approaches that may in later stages be supported by external funds.

132 Graduate School for Health Research SHARE Self evaluation 2003-2008 Table 3 provides the proportion between internal funding ( tenured staff ) and externally obtained resources ( other research input ). An overview of large projects acquired will be presented hereafter in section 6: Earning capacity. Table 3 Funding 2003 2004 2005 2006 2007 2008 % % % % % % Tenured staff 268.920 55 283.460 53 274.032 42 394.892 56 455.060 54 527.984 42 Other research input 218.532 45 252.198 47 379.857 58 314.055 44 384.004 46 724.999 58 Total 487.452 100 535.658 100 653.889 100 708.947 100 839.064 100 1.252.983 100 Finally, international collaboration has been extended the group collaborates in relevant European networks (such as EUROCAT, GENECURE, SAR), and has many research activities in collaboration with research groups abroad (details are provided in section 3). As shown in section 6, the above-mentioned activities have been quite successful in obtaining grants. Most research grants in the Dutch system are based on PhD projects, which has resulted in a sharp increase in the number of PhD students. Within the Dutch system, the vast majority of scientific publications is generated by PhD students, notably in their third and fourth years. Therefore, a crop of publications will follow in the coming years.

Chapter 5 Evidence Based Medicine in Practice 133 3 Re s e a rch env ironment and embedding In line with the recommendations of the previous review committee, international and national collaboration has been extended. Collaboration with research groups in the Netherlands and abroad has been and is being actively promoted. The preferred operationalization is a MSc or PhD project conducted partly at the University of Groningen and partly abroad. This can include a stay abroad, but also a joint appointment. The latter is facilitated by the Ubbo Emmius scholarship program of the University of Groningen. Moreover, the programs staff members participate in international networks. Active efforts to invite (more) guest researchers is on the agenda for the near future. The result is the following long list, showing the broad range of disease areas and expertise in methodology. Inte rn ation al Collab or ation Networks ESAC/ EARSS EU networks, Use of antimicrobials and resistance. Self-medication with antimicrobial agents European Diabetes Epidemiology Group BBMRI (Biobanking and Biomolecular Resources Research Infrastructure), a FP7 project of the EC EUROCAT, European network of 40 birth defect registries Nuffic /Vietnam, Anti-tuberculosis drugs and Hepatitis B cost-effectiveness EU Network Drugs and Driving and International Council on Alcohol, Drugs and Traffic Safety (ICADTS) Pharmaceutical Care Network EMEA, ENCePP, European Network of Centres for Pharmacoepidemiology and Pharmacovigilance World Mental Health Surveys Collaborative international MSc / PhD projects Slone Epidemiology Institute, Boston University, USA Medical Research Council UK and Cambridge University Steno Diabetes Center, Copenhagen, Denmark Institute of Medical Sociology and Social Medicine, Marburg University, Germany Department of International Health, University of Copenhagen, Denmark Department of Epidemiology and Health Promotion, National Public Health Institute, Finland Pharmacoepidemiology, Bath University, UK Bremen University, Germany School of Pharmacy, London, UK Health Protection Agency (HPA), London, UK University of Ghent, Belgium GMaSol Consultancy, Switzerland Base Case Consultancy Germany University of Nottingham, UK Department of Medical Genetics, St Mary s Hospital, Manchester, UK Genetic, Epidemiology Unit, University of Cambridge and The CHEK2 Breast Cancer Case- Control Consortium, UK University of Maryland, School of Pharmacy, Baltimore, USA University of Ulster, Belfast School of Pharmacy, Prague

134 Graduate School for Health Research SHARE Self evaluation 2003-2008 Tianjin Medical University Cancer Institute and Hospital, School of Public Health, Tianjin Medical University, China Department of Community Medicine, University of Hong Kong George Institute for International Health, University of Sydney N a t i o n a l c o l l a b o r a t i o n Radboud University Nijmegen Medical Centre Utrecht University (Pharmacoepidemiology; Julius Center for Patient Oriented Research, Geriatrics, Dept. of Psychiatry) Leiden University Medical Center (Clinical Pharmacy, clinical decision-making) Amsterdam Medical Center (Clinical Pharmacy, Dept of Infectious Diseases) RIVM (National Institute for Public Health and the Environment) TI-Pharma (Top Institute Pharma) Royal Dutch Society for the Advancement of Pharmacy (KNMP) College ter Beoordeling van Geneesmiddelen Medicines Evaluation Board Netherlands Vaccine Institute Netherlands Diabetes Epidemiology Study Group Ephor (Centre for expertise concerning pharmacotherapy for the elderly) G u e s t r e s e a r c h e r s Prof J Zito (Pharmaceutical Health Services Research Dept., University of Maryland, Baltimore, US) Dr M Nauton (Darwin, Australia) Dr SL Jackson (Dept. of Pharmacy, University of Tasmania, Australia) Dr AJ van Hoek (Health Protection Agency, London, UK)

Chapter 5 Evidence Based Medicine in Practice 135 4 Q u a lit y and scientif i c relev a n ce M o s t r e l e v a n t r e s u l t s A core issue in our mission is to provide scientific evidence for clinical practice. The most relevant results on this issue can be seen in the evidence our group has provided for national clinical guidelines. Specifically, through positions on boards of guideline consortia or committees and participation in invitational conferences and other forums, the relevance of accounting for evidence and information on cost-effectiveness, budget impact and potential implementation scenarios was stressed. This in addition to growing national and international consensus is increasingly convincing key stakeholders such as CBO, NHG, Trimbos, CVZ and the Orde van Medisch Specialisten (Association of Medical Specialists) that evidence on efficacy, clinical or otherwise, is insufficient for considered policy decisions. Development and validation of performance / quality indicators for use by both health professionals (quality assessment and improvement) and policymakers (external quality assessment). Cost-effectiveness information that has been used in guidelines. For example a dynamic approach was developed to assess the cost-effectiveness of infectious diseases control with applications to Chlamydia screening and pertussis vaccination, anxiety & depression, Parkinson s disease, heart failure. The identification of risk factors and their adequate treatment. Examples include the successful implementation of the project ZorgVoor.foliumzuur bij kinderwens in Dutch community pharmacies to improve folium acid use to prevent birth defects, and GP factors associated with sub-maximal drugs treatment in diabetes patients. The identification of predictors of suboptimal treatment resulting in new approaches to implement evidence-based medicine in practice. For example, factors that determine the undertreatment of risk factors in patients with type 2 diabetes has been unraveled in order to develop a new approach to counter so-called clinical inertia. In addition to numerous publications in high level scientific journals (see section 5), these achievements have resulted in the participation of members of the program in many national and international committees devoted to increasing evidence-based medicine in daily clinical practice (details in section 7). Key publication s The following selection of publications shows the application of methodological expertise within the EBM program on a wide range of diseases. All publications have authors from different departments within the program, as well as at least one clinician or pharmacist, illustrating the interaction within the program and with clinical practice. Boersma C, Postma MJ, Visser ST, Atthobari J, de Jong PE, de Jong-van den Berg LTW, Gansevoort RT. Baseline albuminuria predicts the efficacy of blood pressure-lowering drugs in preventing cardiovascular events. British Journal of Clinical Pharmacology 2008;65:723-32. Voorham J, Haaijer-Ruskamp FM, Stolk RP, Wolffenbuttel BH, Denig P. Influence of elevated cardiometabolic risk factor levels on treatment changes in type 2 diabetes. Diabetes Care 2008; 31:501-503. Dolk H, Jentink J, Loane MA, Morris JK, De Jong-van den Berg LTW. Does lamotrigine use in pregnancy increase orofacial cleft risk relative to other malformations? Neurology 2008;71:714-22.

136 Graduate School for Health Research SHARE Self evaluation 2003-2008 Van Roon EN, Flikweert S, Le Comte M, Langendijk PNJ, Kwee-van Zuiderwijk WJM, Smits P, Brouwers JRBJ. Clinical relevance of drug-drug interactions: a structured assessment procedure. Drug Safety 2005;28(11)1131-1139. Vehof J, Postma MJ, Bruggeman R, De Jong-Van Den Berg LT, Van Den Berg PB, Stolk RP, Burger H. Predictors for starting depot administration of risperidone in chronic users of antipsychotics. Journal of Clinical Psychopharmacology 2008;28:625-30. M o s t i m p o r t a n t b o o k s / b o o k chapters Our group has published 24 chapters in books, and has been the editor of two books. The majority of publications in books are in Dutch, a few in English and German. The most relevant are: Dukes MNG, Haaijer-Ruskamp FM, de Jonckheere CP, Rietveld AH, (eds). Drugs and money; prices, affordibility and cost containment. Amsterdam etc, IOS Press, 2003. Buurma H, de Jong-van den Berg LTW, Leufkens HGM, (red). Het geneesmiddel. Maarssen, Elsevier Gezondheidszorg, 2005. New ed. 2009. Haaijer-Ruskamp FM, Andersen M, Vander Stichele R. Prescribing quality indicators. In: Hartzema AG, Tilson HH, Chan KA (eds). Pharmacoepidemiology & therapeutic risk management. Cincinnati, OH, Harvey Whitney Books, 2008: pp. 197-218.

Chapter 5 Evidence Based Medicine in Practice 137 5 Q u a ntit y o f s c i e ntif i c o u t p u t The scientific output of the program can broadly be divided into three categories: publications in peer-reviewed journals, facilities provided for epidemiological and primary care research, and consultancy services to support research by other departments. In contrast to publications (number, impact, etc), facilities and consultancy are more difficult to quantify but are as important to provide high quality study outcomes that result in evidence to guide clinical practice. Publication s tr ateg y The EBM-P program aims to publish its findings in high quality international peer-reviewed journals, while simultaneously reaching the professionals and the general public with publications in national professional journals. The latter is described in section 8, Societal Relevance. The scientific publications in peer-reviewed journals of the program are summarized in the table. We have included publications by the researchers from pharmacoepidemiology, pharmacoeconomics and pharmacotherapy over the entire period, because our collaboration dates from before the formal start of these researchers in our program in 2006. The extension of the program in 2006 with epidemiology and HTA is clearly visible in the numbers. In addition to the increased number of publications, the proportion of papers in high-ranked journals per tenured staff member has also increased. This rise is the result of increased collaboration between members of the group. Another important factor has been the active promoting of a publication strategy of increasing the number of publications in high impact journals within a (S)SCI field, triggered by the comments of the review committee and the general strategy of the UMCG. This includes a more critical policy for submitting papers, with a clear view of the impact factor of the journal. Moreover, active collaboration has been established with international research consortia, as well as individual researchers from other national and international centers, to increase the number of publications. Finally, PhD students (and other researchers if necessary) are trained in scientific writing in English. Since the EBM program focuses on bridging the gap between evidence and practice by using a population-based approach based on common methodological approaches and is not diseasedriven like the ISI fields, publications are in several fields, with an emphasis on cardiometabolic diseases and nephrology. The connections with clinical practice are illustrated by the coverage of topics which represent the current burden of disease in society: Pharmacology & Pharmacy Health Care Sciences & Services Health Policy & Services Endocrinology & Metabolism Geriatrics & Gerontology Cardiovascular System & Cardiology N u m b e r o f p u b l i c a t i o n s Table 4 provides a description of several types of research output. An explanation of the the types distinguished is given in chapter 1. Table 4 also gives the average number of top-30% articles per tenured staff member.

138 Graduate School for Health Research SHARE Self evaluation 2003-2008 Table 4 Output 2003 2004 2005 2006 2007 2008 n % n % n % n % n % n % ISI articles top-30% 18 49 30 54 28 49 60 61 55 57 70 64 other 19 51 26 46 29 51 39 39 42 43 39 36 Total 37 100 56 100 57 100 99 100 97 100 109 100 (top-10%) (8 22) (11 20) (14 25) (30 30) (21 22) (38 35) Other refereed articles 22 41 22 13 14 17 Book chapters 1 9 3 8 3 Books 1 1 PhD theses SHARE theses 5 8 4 5 5 4 Others, (co-)supervised 3 3 2 2 1 # Top-30% articles per 2.5 4.0 3.9 5.8 5.0 5.5 tenured staff member Re s e a r c h f a c i l i t i e s The EBM program offers a number of facilities for epidemiological and primary care research. The emphasis is on collecting and managing (large scale) databases of both population and clinically based populations. These comprise a invaluable tool to perform epidemiological and clinical studies. The EBM program provides both scientists to design, improve and interpret these data, and also technicians to construct and support them. The Trial Coordination Center (TCC) facilitates clinical and other researchers with the design, conduction, analysis and reporting of biomedical research. TCC is an ISO certified organization. Its service operations include project management, protocol writing, data entry, data management, monitoring, statistics, reporting and software development. The GIANTT project (Groningen Initiative to Analyse Type 2 diabetes Treatment) is a regional initiative of health care providers and researchers focusing on the care delivered to ambulant patients with type 2 diabetes mellitus in the north of the Netherlands. The InterAction DataBase (IADB) provides complete prescription data regardless of reimbursement status covering 500,000 patients. The aim is to create a laboratory for research in pharmacoepidemiology, pharmacoeconomics and pharmacy practice management, using prescription data from these pharmacies. EUROCAT birth defect database, covering an approximate total population of half a million births per year. MOC COM is a project at the Family Cancer Clinic and concerns a prospective registration of all patient contacts at this clinic. The aim is to assess the cost-effectiveness of the care provided in an evidence-based way. At the moment a similar project is under construction at the Breast Cancer Clinic.

Chapter 5 Evidence Based Medicine in Practice 139 The LifeLines project is being carried out in a representative sample of 165,000 participants from the northern provinces of the Netherlands. LifeLines will employ a three-generation family design (proband design with relatives). The overall aim is to study universal risk factors and their modifiers for multifactorial diseases. Members of the EBM program are actively involved in the LifeLines project, notably in the scientific committee (chair), data quality, protocol development, data management. The aim of the LifeLines project is to study universal risk factors and their modifiers for multifactorial diseases. LifeLines will employ a three-generation family design (proband design with relatives). For the clinical practice of multifactorial diseases, it is important to understand how similar risk factors relate to multiple diseases, and which modifiers contribute to the development of specific multifactorial diseases, not only at one stage of life but cumulatively over time: the lifeline. During the period of this evaluation, preparations have started to create a large research database based on the medical files of all general practitioners and public pharmacies in the northern part of the Netherlands (Dutch acronym AHON), in collaboration with NHG/ LHV. When completed, this database will contain longitudinal information on more than 1.5 million people. The final measure of scientific output is the effort members of the program put into consultancy services. These involve the methodological support of clinical research, ranging from simple one-off questions (like power calculation, study design, model for costs calculation) to collaborative research proposals or collaborative conducting of a study. A special service is run by the MTA researchers to support researchers who want to submit a proposal to the cost-effectiveness program of the Dutch Organisation for Health Research (ZonMw Doelmatigheid). Training of researchers in the hospital and primary care (notably general practitioners and pharmacists) is an explicit part of the consultancy program. A clear example is the monthly presentation series Help Statistics on various statistical problems, providing handson solutions. Since 2006, there have been around 250 consultations per year performed by the program. In addition, support was provided for almost 25 cost-effectiveness grant proposals per year.

140 Graduate School for Health Research SHARE Self evaluation 2003-2008 Follow-up of patients with breast cancer A s an a s s o c i a t e p r o f e s s o r w i t h i n t h e d i s c i p l i n e g r o u p E p i d e m i o l o g y, Tr u u s ke d e B o c k i s s p e c i a l ize d i n o n c o l o g y a n d h e r m o s t i m p o r t a n t r e s e a r c h a r e a i s b r e a s t c a n c e r. O n e o f h e r c u r r e n t p r o j e c t s f o c u s e s o n f i n d i n g a n o p t i m a l f o l l ow - u p s t r a t e g y f o r p a t i e n t s w i t h b r e a s t c a n c e r. W i t h i n t h i s p r o j e c t, s h e c o l l a b o r a t e s w i t h r e s e a r c h e r We n l i L u, w h o i s a l e c t u r e r a t t h e College o f P u b l i c H e a l t h o f T i a n j i n M e d i c a l U n i ve r s i t y i n C h i n a. She became involved in the project via a Bernoulli scholarship. Over the past four years, the researchers had an intensive cooperation. In the first two years they have been designing a database and collecting follow-up data from medical statuses; Wenli in Tianjin, Truuske in the Netherlands. In addition, Wenli worked on a meta-analysis on the impact of follow-up after breast cancer on survival. In the second two years, Wenli worked on her research in Groningen. The database contains the data of 1000 Chinese and 700 Dutch patients, and Wenli worked on the analysis of both databases. Both researchers are involved in research into the optimal strategy for the follow-up of Chinese and Dutch patients suffering from breast cancer. Baseline data It is estimated that there are 1.15 billion new cases of breast cancer worldwide every year. With regard to this, there is a remarkable difference between Western European countries and China. Where the incidence in Western Europe is roughly 6700 per 100,000 women annually, this figure is roughly 19 per 100,000 women in China. In spite of this low incidence, the absolute number of new cases is high; over 20% of all new cases of breast cancer worldwide are diagnosed in China. Wenli explains that this is mainly due to the size of the population. China has a population of 1.31 billion. In addition, the incidence of breast cancer in China is increasing by 3-4% every year. Another remarkable difference between the Chinese and the Dutch data is the age division. In the Netherlands, the average age at the time of diagnosis is about 58, in China this is 48. Many of the women diagnosed in China are at an advanced stage of the disease. An important explanation for this is the fact that there is no such thing as a national screening program. There are possibilities for screening but the patient nearly always has to pay for this. Often women decide against it. Most of them do not see a doctor until symptoms develop. Wenli adds: It is important to investigate the feasibility of a national screening program in China in the light of the low incidence of breast cancer, the vast population and other socioeconomic aspects.

Chapter 5 Evidence Based Medicine in Practice 141 Treatment and follow-up After the primary treatment, which in China means a total breast amputation in 95% of cases but in the Netherlands only happens in 40% of cases, there are various possible follow-up strategies. The main goal of Wendi s research is to determine the optimal strategy for follow-up after breast cancer. A simulation model will be developed using the data collected in the Netherlands. Recently, Wenli has been examining therapy loyalty to the existing follow-up guidelines in daily practice. The guidelines in Tianjin Hospital state that check-ups should occur every three months during the first two years, every six months from the third to the fifth year and after that annually. In actual practice therapy, loyalty to this guideline turns out to be extremely low; only 4% of the patients undergo all the recommended check-ups during the follow-up period. A slightly higher percentage show up once or twice for a check-up after the initial treatment but then do not follow the guideline schedule. What is the cause of this lack of therapy loyalty? The patients are invited for check-ups but simply do not show up. Wenli distinguishes between a number of possible explanations. First and foremost, there is the Chinese insurance system. Many women have to pay for the check-ups themselves. Furthermore, the long distances to the hospital and the additional time and travel expenses may play a role. In addition, researchers think that women may not consider the check-ups that important. If you look at the reported number of local recurrences (return of the cancer), only 4% in ten years, this is understandable. Continuation The development of a simulation model to realize optimal follow-up for women with breast cancer was an interesting and challenging prospect for the researchers. The research and its international character is very inspiring. Recently, Wenli returned to China. She published three articles in the last two years and she has one submitted manuscript. Now she is working on the last two papers and her thesis. The defense of her thesis is expected to be in March 2010. In April 2010, the researchers plan to meet again to work on a new project in which the simulation model will be validated in the Chinese population to contribute to optimal cancer screening in China.

142 Graduate School for Health Research SHARE Self evaluation 2003-2008 6 E a r n ing capacit y Within the Dutch system, the vast majority of scientific publications is generated by PhD students. Therefore, a large proportion of grant proposals are PhD projects, which results in scientific publications three and four years after commencement. As shown in the table in section 2, over the last years the program has been quite successful in obtaining grants for PhD projects, which has resulted in a steep increase in the number of PhD students. The crop of publications will follow in the coming years. F u n d - r a i s i n g s t r a t e g y Below is an overview of the major research grants obtained by the program over the last five years. It is clear that the program has been very successful in obtaining grants from both national and international sources. The wide range of topics illustrates the fruitful application of common methodology in different diseases, with an emphasis on pregnancy, cardiometabolic diseases and nephrology. The program staff aims to be represented on the funding committees of important funds in order to anticipate (new) funding trends, leading to representation on ZonMw committees and relevant societal bodies (CVZ, CBG). Table 5 provides a list of the major research projects (> 100.000,-), classified by funder. Table 5 Major projects acquired European Committee Driving under the influence of medicinal drugs Guidelines pertaining to psychotropic medicines and driving: dissemination and evaluation The economics of genetic and genomic strategies developed in renal diseases by the GENECURE project Selfmedication with antibiotics Building a knowledge repository for occupational well-being economics research HIS-Screen: Cost-effectiveness of genetic screening strategies Other International funds Therapeutic drug monitoring of antituberculosis agents in Vietnam (Nuffic) Cost-of-illness of Hepatitis B disease and cost-effectiveness of Hepatitis B vaccination in Vietnam (Nuffic) NWO LifeLines DNA Bank: A genomics infrastructure for a population-based cohort of 165,000 individuals ZonMw (National Organisation for Health Research and Development) Pharmacy Coordinated ADE Reducing Efforts For Use in all Levels of Healthcare (CAREFUL) Identifying bottle-necks in integrated care (KNOTs) Effect of computerized decision support on medication safety in hospitals Value of Information Discounting in economic evaluations of drugs Comparison of low-flux hemodialysis and hemofiltration (CONTRAST) Manipulative therapy for shoulder complaints in General Practice

Chapter 5 Evidence Based Medicine in Practice 143 Symptoms of collapse in general practice: The effect of pelvis physical therapy and of a pessary A randomized clinical trial of urinary incontinence in older women: Cost-effectiveness of protocolized assessment and evidence-based treatment National program network for the elderly Prevention of psychosocial problems in the offspring of mothers with symptoms of depression or anxiety during pregnancy: Benefits for mother and child TI Pharma (Top Institute Pharma Research) Connecting BIOMARKERS and proxy-outcomes across different phases of drug development (TI-Pharma Esscher) Scientific and societal drivers of the current drug regulatory environment, perspectives for improvement (TI-Pharma Esscher) Improving patient SAFETY through better risk management (TI-Pharma Esscher) The Dutch health care landscape as a population laboratory (TI-Pharma Mondriaan) CTMM (Center for Translational Molecular Medicine) Biomarkers for the Prediction and Early Diagnosis of Diabetes and Diabetes-related Cardiovascular Complications (PREDICCt) WP7: Validation of Biomarkers Biomarkers for the Prediction and Early Diagnosis of Heart Failure (TRIUMPH) WP 9: Medical Technology Assessment Other national funds Costs and effects of screening for micro-albuminuria (Dutch Kidney Foundation) Costs and effects of screening for macro-albuminuria (Dutch Kidney Foundation) Health economics of blood transfusion safety (Landsteiner Foundation) Communicating risk effectively (CORE) study (CBG Medicines Evaluation Board) Doctors information needs and decision support for drug therapy (CVZ - Health Care Insurance Board) Evaluation and implementation of guidelines on antimicrobial therapy (CVZ - Health Care Insurance Board) Pharmaceutical care practice redesign: Health management aspect and business administration (Royal Dutch Society for the Advancement of Pharmacy, KNMP) The role of physical activity, fitness and personality in development of metabolic risk factors (HanzeUniversity Groningen) Integrated Pharmaceutical care (Royal Dutch Society for the Advancement of Pharmacy, KNMP) Revealing the genetic roots of obesity and type 2 diabetes (Senter Novem / Ministry of Economic Affairs) Drug treatment of diabetes, GIANTT baseline measurement (Menzis, Healthcare Insurer) GIANTT Benchmarking diabetes care in Groningen province (GHC, Groningen General Practice Collective) Cost-effective approaches in avoiding blood transfusion (Ministry of Health) Cost-effectiveness of new vaccinations within the National Program 1, 2 and 3 (Netherland Vaccine Institute) Cost-effectiveness of screening strategies for HIV and Chlamydia (SOA / AIDS foundation) Routine Outcome Assessment for detection and treatment of comorbidities among patients with schizophrenia (Public Mental Health, Drenthe)

144 Graduate School for Health Research SHARE Self evaluation 2003-2008 Pharmaceutical industry Cost-effectiveness of fungal infection prevention (ORTHO Biotech UK) Discounting in cost-effectiveness of vaccines (GSK Bio Rixensart Belgium) Cost-effectiveness analysis of HPV-vaccination (GSK Zeist) Costing of influenza epidemics and dynamic modeling of influenza spread (Sanofi) Cost-effectiveness of pneumococcal vaccination (Wyeth) Cost-effectiveness of antihypertensive treatments (Various companies) Cost-effectiveness of prevention and pharmacotherapy for infectious diseases (GlaxoSmithKline) Research on computer-assisted diabetes risk management (Roche Diagnostics) RUG / UMCG Chronic heart failure, adherence to treatment guidelines and quality of life The consumption of non-prescribed antibiotics in Europe in relation to antimicrobial resistence patterns Can national differences in heart-failure treatment be explained by health system features? Antiepileptics during pregnancy The implications of health preferences and quality of life for prevention and care in elderly Lifestyle, the metabolic syndrome and renal disease Predictive value of quality indicators for diabetes care on patients outcomes Statistical approaches to life course epidemiology Measuring quality of cardiovascular risk management, development and testing of valid and meaningful tools for the doctor Improving cardiovascular risk management in patients with diabetes mellitus using risk information from Electronic Patient Records Drug safety in chronic psychiatric patients Predictive value of quality indicators for diabetes care on patients outcomes Pregnancy and disease modifying anti-rheumatic drugs Improving prescribing and usage of gastroprotective drugs in general practice Identifying organizational barriers and resolutions in thrombolytic therapy for acute ischemic stroke in the North of the Netherlands Communication in the family cancer clinic Cost-effectiveness of periodic mammographic screening of asymptomatic women with elevated risk of breast cancer

Chapter 5 Evidence Based Medicine in Practice 145 7 Ac a d e m i c reput ation Members of the EBM program have been recognized for their scientific achievements in different ways. In the overview below the most relevant scientific signs of recognition are given. A major effort is invested in national organizations, in particular ZonMw, the National Organisation for Health Research and Development which focuses on health services research, as well as the Gezondheidsraad (Health Council of the Netherlands), the independent scientific advisory body whose task it is to advise government and Parliament in the field of public health. Both organizations are well in line with the aim of the EBM-P program with its focus on providing evidence for clinical practice. Besides these scientific committees our research group is highly visible in committees on clinical guidelines and healthcare organizations, as described in section 8 (societal relevance). P r ize s a n d aw a r d s A special award was the Medication Safety Award in 2009 which was given by the NVZA (Dutch Society of Hospital Pharmacists) to J. van Doormaal (PhD student) for her work on the effect of a computerised medication ordering system (CPOE) on medication errors and adverse drug events in hospital. She showed that such a system may prevent medication errors, but not directly adverse drug events. Best podium presentation C Boersma (PhD student), International Society of Pharmacoeconomics and Outcome Research (ISPOR) Best poster Renee Lub (reseracher), International Society of Pharmacoepidemiology (ISPE) 2006 Best poster presentation Willeke Kasje (PhD student), International Society of Pharmacoepidemiology (ISPE) 2004 Best poster presentation M van Hulst (PhD student), International Society of Pharmacoeconomics and Outcome Research (ISPOR) 2007 I nv i t a t i o n s f o r m a j o r l e c t u r e s and conference pre s e n t a t i o n s The program staff held a large number of invited lectures. We have selected a limited number of relevent, representative examples of the senior program staff during 2003-2008 LTW de Jong van den Berg, 14 invited lectures, including: Patterns of prescription drug use in pregnancy, ICBDSR, Malta, 18-09-2005 Reproductive Pharmacovigilance, ToulouseCongres de Physiologie, de Pharmacologie et de Therapeutique (P2T), 11-04-2007 M Postma, 40 invited lectures, including: Cost-effectiveness of Enhanced Blood Donor Recruitment and Extended Viral Screening Policies, CDC/PEPFAR Workshop, Washington, Jan 2006 Future of Pharmacogenetics & -economics, European Society for Clinical Pharmacy (ESCP), Oct 2005 E Buskens Invitational conference youth care on use and usefulness of TA Invitational conference on use and design of TA in elderly care (NPO) P Denig Second national Medication Compliance conference, 2008