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Markus Müller Editor Clinical Pharmacology: Current Topics and Case Studies Second Edition Clinical Pharmacology: Current Topics and Case Studies Markus Müller Editor Clinical Pharmacology: Current Topics and Case Studies Second Edition Editor Markus Müller Universitätsklinik für Klinische Pharmakologie Medizinische Universität Wien Wien Austria ISBN 978-3-319-27345-7 ISBN 978-3-319-27347-1 (eBook) DOI 10.1007/978-3-319-27347-1 Library of Congress Control Number: 2016935068 Springer Cham Heidelberg New York Dordrecht London © Springer International Publishing Switzerland 2016 T his work is subject to copyright. 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Printed on acid-free paper Springer International Publishing AG Switzerland is part of Springer Science+Business Media (www. springer.com) Contents Part I Introduction 1 The Discipline of Clinical Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . 3 Markus Müller 2 Current Issues in Drug Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Markus Müller 3 Current Issues in Drug Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Christa Wirthumer-Hoche and Brigitte Bloechl-Daum 4 Current Topics in Drug Reimbursement . . . . . . . . . . . . . . . . . . . . . . . . 33 Anna Bucsics , Robert Sauermann , and Valerie Nell-Duxneuner Part II Clinical Trials 5 Ethics in Clinical Research. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 Ernst Singer and Christiane Druml 6 Good Clinical Practice (GCP) and Scientific Misconduct . . . . . . . . . . . 61 Brigitte Bloechl-Daum 7 Phase I Studies and First-In-Human Trials . . . . . . . . . . . . . . . . . . . . . . 85 Ulla Derhaschnig and Bernd Jilma 8 Clinical Trials: Interventional Studies . . . . . . . . . . . . . . . . . . . . . . . . . . 97 Michael Wolzt and Stefan Aschauer 9 Observational Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 Harald Herkner and Christoph Male Part III Tools in Clinical Pharmacology 10 Tools in Clinical Pharmacology: Imaging Techniques . . . . . . . . . . . . 139 Martin Bauer and Oliver Langer 11 Pharmacokinetics II: 14C-Labelled Microdosing in Assessing Drug Pharmacokinetics at Phase 0 . . . . . . . . . . . . . . . . . 151 Graham Lappin v vi Contents 12 Current Concepts of Pharmacogenetics, Pharmacogenomics, and the “Druggable” Genome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161 Wolfgang M. Schmidt and Robert M. Mader 13 Pharmacokinetics I: PK-PD Approach, the Case of Antibiotic Drug Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185 Sherwin K. B. Sy and Hartmut Derendorf 14 Epidemiology and Biostatistics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219 Gerhard Garhöfer and Leopold Schmetterer 15 Placebo Effects and Placebo Control in Clinical Trials . . . . . . . . . . . . 233 Johannes Pleiner-Duxneuner P art IV Topics in Clinical Pharmacology 16 Pharmaceutical Drug Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247 Martin Brunner 17 Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265 Markus Zeitlinger 18 Development of Advanced Therapy Medicinal Products: A Case for Early Scientific Advice . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293 Martin Brunner and Bernd Jilma 19 Biologics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305 Bernd Jilma and Markus Müller 20 Generics, Biosimilars, Enantiomers, and Me-Toos . . . . . . . . . . . . . . . 317 Dieter Deforce , George Wade , and Brigitte Bloechl-Daum 21 Orphan Drugs for Rare Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337 Brigitte Bloechl-Daum , Florence Butlen-Ducuing , and Jordi Llinares-Garcia 22 Special Situations, Market Fragmentation II: Sex Differences . . . . . 361 Ghazaleh Gouya 23 Special Situations III: Medicines for Children . . . . . . . . . . . . . . . . . . . 377 Christoph Male About the Authors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393 Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401 Part I Introduction 1 The Discipline of Clinical Pharmacology Markus Müller In its chapter about “Principles of Clinical Pharmacology,” Harrison’s textbook Principles of Internal Medicine 2008 states that “drugs are the cornerstone of mod- ern therapeutics” and that “drug therapy varies widely among individuals” [1 ]. These two statements set the stage for the discipline of clinical pharmacology (CP) which pursues two main goals: (1) an empirical description of conditions under which drug actions vary in humans and (2) to determine and understand the molecu- lar mechanisms underlying this variability [1 ]. Both goals can be pursued (a) scientifi cally, by studying drug action in humans; (b) clinically, by administering appropriate drug therapy to patients; and (c) within a regulatory framework, to pro- vide guidance on the risk/benefi t ratio of drug candidates in drug development and drug reimbursement. H istorically, the discipline of clinical pharmacology was established in several countries as an academic discipline about 40 years ago. Whereas clinical pharmacology was established as a clinical subdiscipline of internal medicine in many countries, experimental pharmacology emerged as a second common trunk for the discipline in others. Hand in hand with its emergence in academia, a substantial number of CP centers were set up in pharmaceutical companies. In 1970 the WHO published an overall document on CP [2 ] to stimulate the development of CP, and in several countries national and international Societies for Clinical Pharmacology and Clinical Pharmacology and Therapeutics were established, e.g., the American Society of Clinical Pharmacology and Therapeutics (ASCPT) and the American College of Clinical Pharmacology (ACCP) in the USA and the European Association for Clinical Pharmacology and Therapeutics (EACPT) in Europe. A SCPT stated its vision as follows: “Clinical pharmacology is recognized and serves as the premier discipline at the forefront of the discovery, development, M. Müller Universitätsklinik für Klinische Pharmakologie , Medizinische Universität Wien , Vienna , Austria e-mail: [email protected] © Springer International Publishing Switzerland 2016 3 M. Müller (ed.), Clinical Pharmacology: Current Topics and Case Studies, DOI 10.1007/978-3-319-27347-1_1 4 M. Müller regulation, and use (DDRU) of safe and effective medications necessary for the prevention and treatment of illness,” whereas the American College of Clinical Pharmacology (ACCP) states: “Promotion of rational use of medications in humans: Innovative research, development and regulation of medications and Education of health care professionals and patients on the optimal utilization of medications.” EACPT was founded after a meeting in Verona in 1991, in an attempt to foster the emerging discipline of CP in the eastern European countries [ 3] . The aims of the Association are to develop clinical pharmacology and therapeutics in Europe by promoting the utilization of clinical pharmacological services in healthcare delivery ( http://www.eacpt.org/?q=node/2 ) . A mong others, the development of CP is driven by various CP Journals, most notably C linical Pharmacology and Therapeutics , Journal of Clinical Pharmacology , British Journal of Clinical Pharmacology , E uropean Journal of Clinical Pharmacology , or the International Journal of Clinical Pharmacology . C P has gone through a number of development cycles. Concomitantly with a steep growth of the pharmaceutical industry, CP experienced an “age of excitement” [4 ] in the 1950s and 1960s which led to the foundation of a large number of CP departments worldwide. According to one of the founders of the discipline, Sir Collin Dollery, clinical drug evalua- tion, which formerly seemed “a matter of gathering testimonials from well-known clini- cians,” is now a well-designed process, and clinical pharmacology has become an indispensable part [ 5] . Although clinical pharmacologists now occupy infl uential positions in the government and regulatory agencies such as EMEA or NICE [4 , 6] , a widespread feeling emerged in the late 1990s that CP may not have lived up to its high expectations [7 – 9 ], and in the UK, the number of clinical pharmacologists has been in decline [7 ], a situ- ation, however, that is contrasted by the sustained growth of CP in other European countries [1 0] . There is no doubt that the lack of “an organ” and a billable procedure [ 8] makes a clinical specialty more vulnerable to oblivion in a world where “added value” is frequently reduced to economic concepts and values of a specifi c brand. The beauty and at the same time “Achilles heel” of CP has always been its enormous breadth, which has expanded further in recent years [ 11 ]. Nobody can reasonably claim to be an expert of drug therapy in all therapeutic areas. Likewise it is not credible to claim mastery of clinical therapeutics if one does not participate in up-to-date care of patients. On the other hand, a substantial portion of today’s specialists, who care for patients on a daily basis, have had insuffi cient training in the principles of pharmacodynamics, pharmacokinetics, pharmacovigilance, epidemiology, drug utilization, and drug development. T he added value of clinical pharmacologists, jointly trained in CP and an organ-based specialty [ 9 ], is that they can bring together these scientifi c principles and specialty practice and ideally can infl uence the colleagues around them. This kind of training model seems to offer the best chance for clinical pharmacology to make an impact in healthcare. Indeed, since most prescribing of medicines occurs in the community, CP should also look toward primary care as a future development opportunity. W e live at an eventful time in clinical science when the powerful new forces of genom- ics, information technology, imaging technology, or economics, to name a few, are rapidly changing the science and art of medicine. In practice, this will require even more specializa- tion than before. However, there is also an increasing demand for a more integrated and holistic [ 9 ] approach, which can pull all the different strands together [6 ] to create “added value” in patient care, drug research, and drug regulation. In this regard, CP has already