New Drugs in General Practice
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NEW DRUGS IN GENERAL PRACTICE PRESCRIBING PATTERNS AND EXTERNAL INFLUENCES Stefan R. Florentinus Cover design: Claudine Florentinus-Stokkel Cover photo: Prof. Andrew Davidhazy. Please visit: www.rit.edu/~andpph CIP-gegevens Koninklijke Bibliotheek, Den Haag Florentinus, Stefan Remco New drugs in general practice / Prescribing patterns and external infl uences / Stefan R. Florentinus Thesis Utrecht - with ref. - with summary in Dutch ISBN-10: 90-393-4261-x ISBN-13: 978-90-393-4261-9 © Stefan Florentinus (stefan@fl orentinus.com) NEW DRUGS IN GENERAL PRACTICE: PRESCRIBING PATTERNS AND EXTERNAL INFLUENCES Nieuwe geneesmiddelen in de huisartsenpraktijk: Voorschrijfpatronen en externe invloeden (met een samenvatting in het Nederlands) Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnifi cus prof. dr. W.H. Gispen, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op donderdag 18 mei 2006 des middags te 2:30 uur door Stefan Remco Florentinus geboren op 22 januari 1977 te Amstelveen, Nederland Promotores Prof. dr. H.G.M. Leufkens Prof. dr. P.P. Groenewegen Copromotores Dr. E.R. Heerdink Dr. ir. L. van Dijk This thesis was part of the UNICA (Utrecht University and NIVEL primary CAre) project; a collaboration between the Division of Pharmacoepidemiology and Pharmacotherapy of the Utrecht Institute for Pharmaceutical Sciences (UIPS) and NIVEL (Netherlands Institute for Health Services Research). This thesis was supported by an unrestricted grant from the Royal Dutch Pharmaceutical Society (KNMP), The Hague, The Netherlands. The study presented in Chapter 4.1 was funded by an unrestricted grant from the Dutch Health Care Inspectorate (IGZ). 6 Be not the fi rst by whom the new are tried, Nor yet the last to lay the old aside. Alexander Pope Voor mijn familie 7 CONTENTS Chapter 1 INTRODUCTION p.11 Chapter 2 DATA USED IN THE UNICA PROJECT 2.1 Linking pharmacy dispensing data to prescribing data p.31 of general practitioners. 2.2 Discrepancies between prescribing and dispensing of p.41 medicines in general practice. Chapter 3 NEW DRUGS IN GENERAL PRACTICE 3.1 Who are the early prescribers of new drugs? p.53 Five cases of rapid market introductions. 3.2 Is new drug prescribing specialist induced? p.67 3.3 The effect of pharmacotherapy audit meetings on p.77 new drug prescribing by general practitioners. 3.4 Which pharmacists contribute to high-level p.87 pharmacotherapy audit meetings with GPs? Chapter 4 CASE STUDIES ON NEW DRUG PRESCRIBING 4.1 Off-label use of the new drug rofecoxib. p.99 4.2 Patient characteristics associated with prescribing of a p.109 newly introduced drug: the case of rofecoxib. 4.3 The trade-off between cardiovascular and gastrointestinal p.115 effects of rofecoxib. 4.4 The use of rosuvastatin shortly after marketing. p.123 Chapter 5 GENERAL DISCUSSION p.129 Chapter 6 SUMMARY / SAMENVATTING p.145 Acknowledgements p.157 References p.160 Curriculum vitae p.188 9 Chapter 1 INTRODUCTION 11 Introduction Introduction Fuelled by chemistry and increasingly guided by molecular biology, drug discoveries are an important pillar of present day medical practice 1,2. The discoveries of, for example, penicillin, cortisone, streptomycin, and chlorpromazine, are just a few defi nitive moments that revolutionised modern medicine 3 . Without the discovery of new drugs, today’s medical practice would probably still be in the pre World War II era characterised by a high mortality rate due to absence of effective antibiotics, vaccines, and many other drugs 3,4. However, despite all positive contributions brought about, every new drug represents a delicate compromise between the promise of healing, the risk of possible side effects, and the price 5 . In response to the drug tragedies with thalidomide and diethylstilbestrol in the 1960s- 1970s 6,7, extensive efforts have been made to establish and optimise drug regulation to ensure the safety, effi cacy, and quality of the new drugs reaching market approval 8,9. Nowadays, new drugs are subjected to extensive clinical testing in randomized clinical trials to ensure relative effi cacy of the new drug entering the market. As important progress has been made both on the development and safety aspects of new drugs, today’s pharmaceutical market place is faced with new challenges, namely a declining rate by which new and innovative drugs become available, increasing (development) costs of the new drugs, and to ensure safe and proper use of new drug in the post-marketing phase 10-15. As most Western countries face an aging population with a high prevalence of morbidity, there is a growing need for safe and effective new drugs 14. The increasing demand for effective and safe new drugs is matched, however, by a declining number of new drugs being introduced on the market every year 14,15. Not only is the overall number falling, so is the number of new drugs that are truly innovative. Most of the drugs that leave the clinical testing phase and enter the pharmaceutical market place are gradual innovations of existing compounds or therapies. The declining output of the pharmaceutical pipeline is paralleled with increasing costs for developing new drugs 16,17. The high costs of new drugs are partly a refl ection of the high- risk investments preceding drug development and the economic pressure on pharmaceutical companies to produce blockbuster drugs (drugs with an annual worldwide sale of $1 billion plus) with the accompanying marketing efforts to ensure suffi cient market share 18. In 2002, the worldwide sales of prescription drugs exceeded $430 billion, of which 85 percent was spend in North America, Europe, and Japan 19. The high development costs of new drugs give rise to concerns about the budget impact of new drugs on the consistently rising national health expenditures 14,15,17,20,21. As the price of new drugs is in general higher than that of similar compound belonging to the same drug class, new drugs place pressure on the sustainability of our welfare state, but also on free market healthcare systems such as in the US 21. 13 Chapter 1 Despite the enormous improvements in drug regulations, there is still a high degree of uncertainty at the moment of market introduction about the new agent’s surplus value in daily clinical practice 22,23. This uncertainty not only applies to the new drug’s effectiveness, but also to its safety profi le when used in large populations 24-26. Although new drugs are nowadays relatively safe when they receive market authorisation several new drugs such as among others tolcapone (withdrawn in 1998) 27, mibefradil (1998) 28, cerivastatin (2001) 29, and rofecoxib (2004) 30 were withdrawn after being on the market for only a few years. When new drugs show erratic market uptake, there may be valid concern about uncertain risk-benefi t for patients, suboptimal allocation of fi nancial resources in health care, and possible market withdrawal of new drugs that could have been prevented 25,26,31,32. To understand the dynamics of new drug prescribing, insight in the reasons of general practitioners (GPs) to adopt new drugs, and the underlying mechanisms, is important. GPs play a major role in (long term) drug prescribing and in many countries GPs are the cornerstone of primary healthcare, especially in the UK and The Netherlands where they function as gatekeepers for hospital care. In addition, compared to medical specialists who are often regarded as the early prescribers of new drugs, GPs treat a large and diverse patient population that may contribute to a wide range of patients being treated for an array of different indications. The phenomenon of new drug prescribing is composed of a micro-level component, i.e. the decisions of individual GPs in a specifi c doctor-patient encounter, and a macro-level component, that is the aggregation of these micro-level decisions into a pattern of diffusion of new drugs. Numerous factors, on both micro- and macro-level, infl uence the probability that a GP adopts a new drug, making the topic very complex. Previous studies on prescribing of new drugs by GPs. The following section will provide an overview of the literature on prescribing of new drugs by GPs. To organise the literature we use a theoretical model in which the encounters between individual GPs and patients during their private consultations are the basis of the model (Figure 1), as is illustrated by the central part (A) of the model. Notwithstanding the possibility that a group of GPs has collectively decided to use a new drug, the actual decision to prescribe is taken in a specifi c GP patient encounter. The aggregation of these decisions builds the diffusion patterns of new drugs in general practice. This is the outcome of the model and represented by right part (B) of the model. Ideally, the decision to prescribe a new drug is the outcome of a shared decision making process, based on the scientifi c evidence and the medical need of the patient. However, in daily medical practice the context of these encounters and the characteristics of both the patient and the GP are important determinants of the decision whether a drug will be prescribed and if so, which specifi c drug it will be. 14 Introduction The diffusion of new drugs is not solely the summation of the outcomes of the GP-patient encounters. External infl uences of, among others medical specialists, community pharmacists, or pharmaceutical companies, shape the contexts within wich the decisions are made. Besides, medical specialists also have a direct infl uence through their own prescribing and subsequent repeat prescribing by GPs. The external infl uences are illustrated in the left part (C) of Figure 1.