f} SpringerWienNewYork

Transcription

1 f} SpringerWienNewYork

2 Markus Muller Editor Clinical Pharmacology: Current Topics and Case Studies

3 Univ.-Prof. Dr. Markus Miiller Professor and Head of Department, Medical Un iversity Vienna, Vienna, Austria This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically those of translation, reprinting, re-use of illustrations, broadcasting, reproduction by photocopying machines or similar means, and storage in data banks. Product Liability: The publisher can give no guarantee for all the information contained in this book. This does also refer to information about drug dosage and application thereof. In every individual case the respective user must check its accuracy by consulting other pharmaceutical literature Springer-VerlaglWien Printed in Austria Springer- Verlag Wien New York is part of Springer Science + Business Media springer.at Typesetting: Thomson Press (Indi a) Ltd., Chennai, India Printing: Holzhausen Druck GmbH, 1140 Wien, Austria Printed on acid-free and chlorine-free bleached paper SPIN: With 45 (partly coloured) Figures Library of Congress Control Number: ISBN SpringerWienNewYork

4 CONTENTS List of Contributors XIX SECTION 1: Introduction Chapter 1 The discipline of Clinical Pharmacology (Markus Muller) 3 Chapter 2 Current issues in drug development (Markus Muller) 7 1 Historical success 7 2 The dawn of a molecular era) the "druggable genome" and market fragmentation 8 3 Innovation and stagnation 10 4 The development of EBM methodology 12 5 Issues in preclinical and clinical drug development Target and drug candidate identification Preclinical drug development Clinical drug development 13 6 The role of academic medicine 15 7 Confidence crisis and public opinion 15 8 Conclusion 16 Case Study: Pfizer 16 Chapter 3 Current issues in drug regulation (Marcus Muller, Hans-Georg Eichler) 19 1 The drug regulators' decision-making 19 2 Authorizing a medicinal product in the EU The Centralized Authorization The Mutual Recognition Procedure (MRP) and the Decentralized Procedure (DCP) The national procedure 24 v

5 3 Regulatory life-cycle management of medicinal products From efficacy to post-marketing relative effectiveness assessment Pharmacovigilance and signal detection Risk management plans (RMPs) When should a medicinal product be authorized? 28 Case Study: Efalizumab (Raptiva) 29 Chapter 4 Current issues in drug reimbursement (Anna Bucsics) 33 1 Introduction 33 2 Reimbursement principles in general 34 3 Relative effectiveness - background 35 4 Relative effectiveness case study - data submitted for reimbursement in Austria (Anna Bucsics, Valerie Nell-Duxneuner) Introduction Methods Results Interpretation 38 5 MEDEV - local payers vs. global payers 38 6 The Pharmaceutical Forum 39 7 Results Good principles Data for relative effectiveness assessment Networking 44 8 Looking forward EUnetHTA USA - comparative effectiveness research 45 9 In the future - building a european system of assessing relative effectiveness Developing the methodology Validating estimates of relative effectiveness Designing and performing the studies we need Leading the way 47 SECTION 2: Clinical Trials Chapter 5 Ethics in clinical research (Ernst Singer, Christiane Druml) 53 1 Development of world-wide standards in clinical research ethics 53 2 Research Ethics Committees today - function and composition 56 VI

6 3 Research Ethics Committees - issues of debate Increasing workload 57 4 Compensation for committee members 59 Case Study: "Roaring sixties" in clinical research - The Beecher Article 59 Chapter 6 Good Clinical Practice (GCP) and scientific misconduct (Brigitte Bloechl-Daum) 63 1 Introduction 63 2 Historic background The Prussian directive and the case of Neisser The Neisser case Federal Food and Drugs Act of The sulfanilamide disaster and the "Food, Drug and Cosmetic Act", Second WorId War crimes Unit Nazi experiments Nuremberg trial and Nuremberg Code Thalidomide (contergan) tragedy Declaration of Helsinki 66 3 Development of Good Clinical Practice Guidelines 66 4 International Conference of Harmonization (ICH) ICH parties European Commission - European Union (EU) European Federation of Pharmaceutical Industries and Associations (EFPIA) US Food and Drug Administration (FDA) Pharmaceutical Research and Manufacturers of America (PhRMA) Ministry of Health, Labour and Welfare, Japan (MHLW) Japan Pharmaceutical Manufacturers Association (IPMA) ICH observers ICH Steering Committee 69 5 ICH TOPIC E6,Note of Guidance for Good Clinical Practice (CPMP/ICH/135/95) the Principles of ICH GCP 69 6 The three "main players" of ICH-GCP - Ethics Committee, Investigator and Sponsor 70 VII

7 6.1 Institutional review board/indep endent Ethics Committee (IRB/IEC) Investigator Investigator's qualifications and agreements Adequate resources Medical care of trial subjects Communication with IRB/IEC Compliance with protocol Investigational product( s) Randomization procedures and unblinding Informed consent of trial subjects Should study participants receive payment? Should there be a different standard for paying healthy subjects as opposed to patient-subjects? Patient information The informed consent process Records and reports Case record form (CRF) Archiving Progress reports Safety reporting Serious adverse event Suspected unexpected serious adverse event (SUSAR) Causality assessment Premature termination or suspension of a trial Final reports Sponsor Quality assurance and quality control Additional responsibilities of the sponsor 80 7 Deficiencies of GCP Is ICH-GCP just a "bronze standard"? ICH-GCP and academic research 81 8 Summary 81 Research misconduct 82 1 What is research misconduct? 82 2 Forms of research misconduct 82 3 How common is research misconduct or fraud? 83 4 Conclusion 84 Case Study: Medical research in a global world 84 VIII

8 Chapter 7 Phase-I studies and first-in-human trials (Uila Derhaschnig, Bernd lilma) 89 1 Introduction 89 2 Definition phase I 89 3 General considerations for phase- I studies, trial design and study protocol 91 4 Preclinical development 91 5 Choice of subjects, study population 92 6 Dose finding 93 7 Route and rate of administration 93 8 Clinical environment 94 Case Study: Anti-CD28 antibody first-in-man trial 95 Chapter 8 Clinical trials - interventional studies (Michael Wolzt, Stefan Aschauer) Introduction Types of clinical trials Purpose Definition Randomization The basic idea, like most good things is very simple Simple randomization Permuted block randomization Stratified randomization Pseudo - randomization Allocation concealment Blinding Human behaviour is influenced by what we know or believe Different study designs Parallel group design Cross-over design Factorial design Study endpoint Interim analyses 109 Case Study: The cardiac arrhythmia suppression trial (CAST) 110 IX

9 Chapter 9 Observational studies (Harald Herkner, Christoph Male) Introduction Methodological principles Study population Data sources Exposure Outcome Measurement issues Measures of association and impact Interpreting an effect: bias, confounding, and sampling error Bias Confounding Sampling variation Overview of study design types Descriptive studies Analytical study designs Cross-sectional study Cohort study - principles and practical example Case-control study - principles and a practical example The cases The controls and the source population Measurement of the main exposure factor Handling potential confounders Analysis and results Summary of case control studies Case-crossover studies Meta-analysis of observational studies 135 Case Study (cohort study): The risk of venous thrombosis in users of hormonal contraception 135 Chapter 10 Pharmacokinetics I: PK-PD approaches - antibiotic drug development (Sreedharan N. Sabarinath, Rajendra Pratap Singh, Hartmut Derendorj) PK-PD approach Microdialysis for measuring free drug concentrations MD calibration methods MD and tissue penetration of antibiotics Microdialysis and PK-PD 150 x

10 6 Kill curves Experimental settings of in vitro models Conclusion 154 Chapter 11 Pharmacokinetics II: 14C-Iabelled microdosing in assessing drug pharmacokinetics at Phase-O (Graham Lappin) Origins of 14C-Iabelled tracers Administration of 14C_drugs to humans Accelerator Mass Spectrometry The emergence of microdosing Application of microdosing Pharmacokinetic linearity Microdosing and metabolism Conclusions 165 Chapter 12 Epidemiology and bio statistics (Gerhard Garhofer, Leopold Schmetterer) Introduction Measures of the disease frequency Prevalence Incidence Mortality Relationship between prevalence, incidence and mortality Survival analysis Censured data Case fatality rate Risk, relative risk and attributable risk Epidemiologic study designs Statistical measures Why use statistics? Variables Presentation of variables Population and sample Hypothesis testing and the p value Post hoc analysis or "fishing for results" Multiple testing Correlation analysis Association and causation 178 XI

11 Association strength Temporal relationship Dose-response relationship Constancy Plausibility Experiment Specificity 179 Case Study: Multiple post-hoc comparisons in the "Second International Study of Infarct Survival (ISIS-2)" 179 Chapter 13 Placebo effects and placebo control in clinical trials (Magdalena Pilz, Johannes Pleiner) The recent debate about research ethics in placebo controlled trials (PCTs) Placebo vs. active control The issue of "assay sensitivity" Placebo controlled trial: ethical or not? Criteria for justification of placebo 186 Case Study: Placebo Surgery 187 SECTION 3: Tools in Clinical Pharmacology Chapter 14 Tools in clinical pharmacology - imaging techniques (Martin Bauer, Oliver Langer) Introduction Positron emission tomography (PET) Single photon emission computed tomography (SPECT) Optical imaging Magnetic resonance imaging (MRI) Computed tomography (CT) Ultrasound imaging 200 Case Study: Using PET in drug development - aprepitant 200 Chapter 15 Current concepts of pharmacogenetics, pharmacogenomics, and the "druggable" genome (Wolfgang M. Schmidt) 205 Xli Genetic variation in the human genome: biological basis of pharmacogenetics 206

12 2 The promise of pharmacogenetics, pharmacogenomics, and genomic medicine Genetic variants affecting pharmacokinetics Pharmacogenetic testing for optimizing drug dose Pharmacogenetic testing to prevent adverse drug reactions Genetics of pharmacodynamics The predictive power of pharmacogenomics The "druggable" genome Challenges that lie ahead 218 Case Study: The abacavir example of successful clinical incorporation of genetic testing 219 Chapter 16 Biomarkers (Volker Wacheck) Introduction Why do molecular targeting drugs fail in current clinical drug development? Biomarker in clinical drug development How biomarkers may improve clinical drug development Biomarker as surrogate endpoints Outlook 236 Case Study: Cholesterol as biomarker and surrogate endpoint for cardiovascular disease 237 Chapter 17 Molecular tools in drug research - translational medicine (Sandra Eder, Volker Wacheck) Introduction Molecular tools for drug target identification At the nucleotide level At the protein level Molecular tools for target validation Target (over)expression Target downregulation Conditional target regulation Molecular tools for monitoring pharmacodynamics in translational studies 255 Case Study: Re-translational studies - the case of ACE2 258 XIII

13 SECTION 4: Topics in Clinical Pharmacology Chapter 18 Pharmaceutical drug safety (Martin Brunner) Introduction Thalidomide - a disaster as starting point for the methodical assessment of drug safety During drug development only frequent ADRs can be detected ADR reporting and worldwide pharmacovigilance Spontaneous reporting systems Drug safety issues after Lipobay and Vioxx Recent and future developments in pharmacovigilance Conclusions 274 Case Study 1: Cerivastatin - the withdrawal of a blockbuster drug is needed to expose problems with drug safety systems 274 Case Study 2: Micafungin - safety issues prompt EMA to demand submission of a risk management strategy as a condition of market authorization in the European Union (if not otherwise specified, the EMA public assessment report, EPAR [38] was quoted) 276 Chapter 19 Drug interactions (Markus Zeitlinger) Definition Relevance of interactions Categories of interaction Factors promoting interactions and their clinical relevance Most important mechanisms of interactions according to the ADME schemata ADME - interactions based on drug absorption ADME - interactions based on drug distribution ADME - interactions based on drug metabolism Examples for clinically relevant interactions based on CYP3A ADME - interactions based on drug excretion Management of potential drug interactions 297 Case Study: Interactions based on a drug class: antibiotics 298 XIV

14 Chapter 20 "Non-chemical" drugs: biologicals, protein therapeutics, vaccines and antisense therapeutics (Markus Muller) Introduction A need for alternatives to traditional chemicals Specifics of the development process of biologicals Protein therapeutics (PTs) Vaccines (group III PTs) Antisense approaches and aptamers 317 Case Study: Alzheimer vaccine 318 Chapter 21 Development of Advanced Therapy Medicinal Products a case for early scientific advice (Bernd lilma) Introduction Cell-based medicinal products (CBMPs) Efficacy and safety challenges Patient integration Characterization Gene therapy medicinal products (GTMP) Development challenges and strategies to address them Vector manufacture Achieving stable gene expression Clinical efficacy and safety Combined ATMPs Involvement of CAT in ATMP development 329 Definitions of Advanced Therapy medicinal products in the European Pharmaceutical legislation) 330 Tasks of the CAT 331 EMA information and guidelines 332 Chapter 22 Individualized medicine (Markus Muller) The current concept A history of dose individualization Pharmacogenetics and biomarkers 338 XV

15 4 The unmet need - improving the benefit-risk ration and effectiveness of drugs Improving the benefit/risk profile by biomarker tests 340 Case Study: Warfarin dosing 342 Chapter 23 Generics, biosimilars, enantiomers and me-toos (George Wade, Brigitte Bloechl-Daum) 345 Generics Regulatory background Patent protection, data protection and marketing protection for new products Salts, esters Bioequivalence Bioequivalence - some special issues Narrow therapeutic index drugs (NTIDs) Highly variable drug products (HVDP) Chiral drugs, enantiomers t max Drugs which are not orally absorbed Inhaled drugs Bioequivalence of intravenous products? complex parenterals Biosimilars Complexity Biosimilars: General issues Regulatory experience Enantiomers Sophisticated nonsense? Rationale for the development of chirally pure drugs Pharmacodynamic and kinetic differences between enantiomers Recent regulatoryexperience of the Chiral Switch: a word of caution Me-toos Background What are "me-too" drugs? How many "me-too" drugs are enough? Is First-in-class also best-in-class? Are incentives for drugs that are "first in class" or hurdles for "me-too" drugs called for? 365 XVI

16 4.6 What is a drug class? Is there a "class effect"? 366 Case Study: Class effect with proton pump inhibitors 366 Chapter 24 Special situations, market fragmentation I: orphan drugs for rare diseases (Brigitte Bloechl-Daum, Florence Butlen-Ducuing, lordi Llinares-Garcia) What are rare diseases? What are orphan drugs? The orph an drug legislation The Committee on Orphan Medicinal Products (COMP) Orphan incentives What are the criteria for orphan designation? General requirements for a valid condition for orphan designation What data are necessary at the time of Orphan Drug designation? Some examples for a positive opinion for orphan designation Negative opinion s Reason for negative opinions - subsetting - no significant benefit Subsetting/valid condition Significant benefit Confirmation of orph an status at the time of marketing authorization Challenging marketing exclusivity for orphan medicinal products Success of the orphan programme 379 ILl Designated orph an medicines Marketing authorizations for orphan medicines Discussion Useful links 385 Chapter 25 Special situations, market fragmentation II: sex differences (Ghazaleh Gouya) Expanding scope of gender and sex differences Sex versus gender Sex matters Physiologic variability Pharmacokinetics - sex differences Pharmacodynamic - sex differences Female specific aspects Adverse drug reactions 390 XVII

17 3.6 Clinical trials - women's representation History Barriers of participation in clinical trials Regulatory changes to include women in clinical trials Pregnancy From sex differences to individual differences: where the science is taking us 393 Case Study: Cardiovascular disease and women 393 Chapter 26 Special situations III: Medicines for Children (Christoph Male) Children as therapeutic orphans Hurdles to drug development for children Ethical and legal aspects Lack of public acceptance Methodological challenges of clinical studies in children Lack of research infrastructures and paediatric research networks Low economic potential of paediatric indications for pharmaceutical industry Regulatory initiatives to improve paediatric drug development Paediatric initiatives in the USA EU Paediatric Regulation Requirements and rewards Paediatric Investigation Plan Paediatric Committee Collateral measures Points to consider for a Paediatric Investigation Plan Paediatric indications Child-appropriate formulations Iuvenile animal studies Clinical Pharmacology studies in children Clinical efficacy and safety studies 412 Case Study: Paediatric Investigation Plan for Clopidogrel 413 About the authors 419 Keyword index 427 XVIII

18 LIST OF CONTRIBUTORS Stefan Aschauer Wahringer Giirtel Martin Bauer Wahringer-Giirtel Brigitte Bloechl- Daum Associate Professor and Deputy Head of Department Wahringer Giirte Martin Brunner Wahringer-Giirtel XIX

19 List of Contributors Anna Bucsics Deputy Head of the Department for Pharmaceutical Affairs Main Association of Austrian Social Security Institutions Kundmanngasse Vienna, Austria anna.bucslcstehvb.sozvers.at Florence Butlen-Ducuing European Medicines Agency 7 Westferry Circus, Canary Wharf London E14 4HB, UK Hartmut Derendorf Department of Pharmaceutics P.O. Box , JHMHC 1600 SW Archer Road Gainesville, FL 32610, USA hartmut@cop.ufl.edu Ulla Derhaschnig Associate Professor of Internal Medicine Wiihringer Giirtel ulla.derhaschnig@meduniwien.ac.at Christiane Druml Chair of the Austrian Bioethics Commission Spitalgasse 23 christiane.druml@meduniwien.ac.at Sandra Eder Section of Experimental Oncology Molecular Pharmacology Waehringer Guertel Sandra.Eder@meduniwien.ac.at xx

20 list of Contributors Hans-Georg Eichler Senior Medical Officer European Medicines Agency 7 Westferry Circus, Canary Wharf London E14 4HB, UK hans-georg.eichler@ema.europa.eu Gerhard Garhofer Wahringer Giirtel Wien, Austria gerhard.garhoefer@meduniwien.ac.at Ghazaleh Gonya Wah ringer Giirtel ghazaleh.gouya@meduniwien.ac.at Harald Herkner Associate Professor of Internal Medicine Department of Emergency Medicine Wahringer Giirtel harald.herkner@meduniwien.ac.at Bernd Iilma Associate Professor and Deputy Head of Department Wahringer Giirtel bernd.jilma@meduniwien.ac.at XXI

21 List of Contributors Oliver Langer Associate Professor of Radiopharmaceutics Wahringer Giirtel Graham Lappin Xceleron Ltd, Innovation Way York YOlO SNY, UK Iordi Llinares-Garcia European Medicines Agency 7 Westferry Circus, Canary Wharf London E14 4HB, UK Christoph Male Associate Professor of Paediatrics Department of Paediatrics Medical University Vienna Wahringer Giiertel christoph.male@meduniwien.ac.at Markus Muller Professor and Head of Department Wahringer Giirtel markus.mueller@meduniwien.ac.at Marcus Miillner AGES PharmMed, Head of Agency Austrian Medicines and Medical Devices Agency Schnirchgasse Vienna, Austria marcus.muellner@ages.at XXII

22 List of Contributors Johannes Pleiner Vienna University School of Medicine Wahringer Giirtel Sreedharan Nair Sabarinath Department of Pharmaceutics P.O. Box , JHMHC 1600 SW Archer Road Gainesville, FL 32610, USA Leopold Schmetterer Associate Professor of Clinical Pharmacology Wahringer Giirtel Wolfgang M. Schmidt Neuromuscular Research Department Center of Anatomy & Cell Biology Wahringer Strafse 13 Ernst Singer Ethics Committee of the Rajendra Pratap Singh Department of Pharmaceutics P.O. Box , JHMHC 1600 SW Archer Road Gainesville, FL 32610, USA XXIII

23 List of Contributors Volker Wacheck Section of Experimental Oncology Molecular Pharmacology Wahringer Giirtel Michael Wolzt Associate Professor and Head, Section Cardiovascular Medicine Wahringer Giirte Markus Zeitlinger XXIV