Psychopharmacology Series 8
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1 Psychopharmacology Series 8
2 Methodology of the Evaluation of Psychotropic Drugs Edited by O. Benkert, W. Maier, and K. Rickels With 19 Figures Springer-Verlag Berlin Heidelberg New York London Paris Tokyo Hong Kong
3 Professor Dr. med. OTTO BENKERT Priv.-Doz. Dr. med. WOLFGANG MAIER Klinikum der Johannes Gutenberg-Universitat Mainz, Psychiatrische Klinik und Poliklinik, Untere Zahlbacher StraBe 8, 6500 Mainz, FRG KARL RICKELS, M.D. University of Pennsylvania, Department of Psychiatry, 203 Piersol Building, University Hospital, 3400 Spruce Street, Philadelphia, PA , USA Vols. 1 and 2 of this series appeared under the titel "Psychopharmacology Supplementum" ISBN-13: DOl: / e-isbn-13: Library of Congress Cataloging-in-Publication Data Methodology of the evaluation of psychotropic drugs leditors,o.benkert,w.maier,k.rickels.p.cm. -- (Psychopharmacology series; 8) ISBN-13: (U.S.:a1k.paper)1.Psychotropic drugs--testing. 2. Clinical trials. I. Benkert, O. II. Maier, W. (Wolfgang). III. Rickels, Karl. IV. Series. [DNLM: 1. Clinical Trials--methods. 2. Psychotropic Drugs. WI PS773J v. 81 QV 77 M592j RM315.M '.788--dc20 DNLMlDLC for Library of Congress. This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, re-use of illustrations, recitation, broadcasting, reproduction on microfilms or in other ways, and storage in data banks. Duplication of this publication or parts thereof is only permitted under the provisions of the German Copyright Law of September 9, 1965, in its current version, and a copyright fee must always be paid. Violations fall under the prosecution act of the German Copyright Law.. Springer-Verlag Berlin Heidelberg 1990 Softcover reprint of the hardcover 1 st edition 1990 The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product Liability: The publisher can give no guarantee for information about drug dosage and application thereof contained in this book. In every individual case the respective user must check its accuracy by consulting other pharmaceutical literature. Typesetting: International Typesetters Inc., Makati, Philippines 2125/3130(3011) Printed on acid-free paper
4 Preface The idea of placebo-controlled drug trials and the advent of test statistics during the first part of this century were the major milestones in the establishment of a convincing methodology for demonstrating the efficacy of treatments. The first tricyclic and neuroleptic drugs were tested for their efficacy in psychiatric disorders along the lines of these methodological developments, but subsequent trials with psychotropic drugs did not adhere to these principles to the same extent because it became difficult to justify placebo-controlled trials once effective treatments had been established. Consequently, the second generation of antidepressants and neuroleptics (since the early 1960s) were mainly tested, in Europe at least, in samples of patients using trials controlled by standard treatment only, and the methodological basis of these second generation trials became fragile, as will be demonstrated by several papers in this book. This development did not provoke much discussion until recently, when scientific and administrative interest in the methodology of the evaluation of psychotropic drugs increased substantially. A series of factors contribute to the growing interest in the standards of psychotropic drug trials: 1. The proportion of psychiatric patients resistant to treatment is growing; the efficacy of well-established forms of treatment therefore seems to be limited. 2. A series of psychotropic drugs were withdrawn from the market, mainly because they caused serious side effects. The efficacy and safety ofthese drugs had previously been demonstrated in drug trials, which raised the question whether the drug trials carried out were well-designed. 3. Some psychotropic drugs introduced as efficacious treatments do not meet clinicians' expectations with regard to their efficacy. 4. The number of conditions to be treated with psychopharmacological drugs is increasing. Panic and eating disorders, for example, used to be mainly treated with psychotherapy, but recent opinion increasingly considers them responsive to psychopharmacological treatment. 5. The legal and administrative regulations for the advission of psychotropic drugs are very different in different countries: in the United States, for example, the conditions are stricter than in West Germany (e.g., with respect to the need for placebo-controlled trials). The European Community will be given responsibility for licensing new drugs in Europe in 1992, making it necessary for the national administrative and legal rules in Europe to be standardized.
5 VI Preface 6. The ethical situation of psychotropic drug trials is becoming more and more complicated. It becomes harder to justify new drug trials the more effective treatments already exist. Additional ethical criteria to be applied differ according to nation. 7. The number of patients available for drug trials is decreasing for a variety of reasons, including a higher refutation rate and the increased number of inpatients refractory to standard outpatient treatment. Other limitations concerning treatment are equally relevant in current drug trials (e.g., long duration of pretreatment, need for concomitant treatment). 8. Methodological problems have been recognized as inherent in the current state of psychotropic drug trials, but simple solutions to these problems are not available. 9. The methodology of testing the efficacy of some kinds of psychotropic drugs (e.g., nootropics - cognition-enhancing drugs) is extremely controversial. The administration of a drug in the treatment of patients requires the clinical efficacy and safety ofthe drug to have been demonstrated prior to use. It is evident that the process of testing drug efficacy should be standardized for each category of drugs (antidepressants, anxiolytics, neuroleptics, hypnotics, nootropics), but methodological standards for testing the therapeutic efficacy of a drug have changed substantially since the first tricyclic antidepressant and neuroleptic drugs were introduced. Therefore, the existence of criteria for establishing efficacy unique to each category of psychotropic drugs is open to discussion. In this book, the editors have attempted to describe the present state of the art and to indicate unsolved and controversial problems, and have proposed solutions for the evaluation of psychotropic drugs. Unfortunately, any overview on problems and possible solutions is not perfect. Drug trials in clinical settings (late phase II or phase III) are the focus of all contributions; it was not intended to discuss preclinical trials. The first four chapters on antidepressants, anxiolytics, neuroleptics, hypnotics, and nootropics are devoted to the current standard of drug evaluation for each ofthese categories of drugs, with particular regard to the current status in terms of selection criteria, length of drug trials, measures of efficacy, and the need for placebo-controlled trials. The drugs able to serve as active treatment controls are identified and recommendations to overcome the methodological flaws of the current drug evaluation studies are given. These presentations of the current state of the evaluation of psychotropic drugs are not intended to be exhaustive; the four chapters discuss mainly controversial issues of current interest. A series of conditions currently being tested for their response to psychotropic drugs are not included in these overviews (e.g., obsessive-compulsive disorder, eating disorder, somatization disorders). The chapter by Crook on the evaluation of nootropic drugs includes a proposal for the measurement of efficacy in cognition enhancing Drugs. Levine subsequently discusses the current strategies in the ascertainment of side effects in clinical trials. The chapter by Paykel on placebo-controlled drug studies in depression demonstrates the feasibility of placebo use, defines the need for it, and identifies
6 Preface VII indicators for these kinds of studies. The chapter on the design of drug trials by Helmchen focuses on the ethical implications involved and proposes guidelines for the selection of inclusion and exclusion criteria and for determining the duration and conduct of treatment in controlled trials. Biostatistical issues which should be taken into consideration in designing and evaluating drug trials are discussed in a chapter by Lavori, which focuses on requirements for sample size and for handling drop outs in evaluating drug trials. The psychopathological aspects of drug trials relevant to the measurement of efficacy and to the definition of selection criteria are the topic of four chapters. Two of them are dedicated to the measurement of drug effects as defined by psychopathological items (Maier, Bech), one discusses diagnosis as selection criteria of drug trials (Buller), and the chapter by Benkert presents new conceptual developments in classifying psychiatric patients according to their response to treatment and the consequences of these developments for the identification of drug-responsive patients. The concluding chapter by Miiller-Oerlinghausen provides an overview of the current status of guidelines proposed by various international committees. The relevance and justification of such guidelines remains an unsolved issue, however, which cannot be discussed extensively in this monograph. The majority of the chapters of this book were based on presentations given in a symposium on the "Methodology of the Evaluation of Psychotropic Drugs" on the occasion of the congress of the Collegium Internationale Neuropsychopharmacologicum (CINP), August 1988 in Munich. The editors hope that this book will be of interest to clinicians and psychopharmacologists interested in familiarizing themselves with the current state of the art in the method010gy developed to test the efficacy of psychotropic drugs. Mainz and Philadelphia, Spring 1990 O. BENKERT, W. MAIER, and K. RICKELS
7 Contents State of the Art in Drug Trials Evaluating Antidepressants and Anxiolytics. K. RICKELS. With 1 Figure... 3 Testing the Efficacy of New Neuroleptic Drugs. S.R. HIRSCH and T.R.E. BARNES. With 5 Figures Evaluation of Drugs in Alzheimer's Disease and Age-Associated Memory Impairment. T.H. CROOK, B.A. JOHNSON, and G.J. LARRABEE. With 3 Figures 37 Testing the Efficacy of New Hypnotic Drugs. F. HOHAGEN and M. BERGER. With 3 Figures Placebo-Controlled Trials and Ethical Issues Placebo-Controlled Studies in Depression: Necessity and Feasibility. E.S. PAYKEL. With 3 Figures Ethical Problems and Design of Controlled Clinical Trials. H. HELM CHEN... ' Biostatistics and Measurement of Drug Effects Statistical Issues: Sample Size and Dropout. P. LA VORl. With 3 Figures Measuring the Efficacy of Psychotropic Drugs: Clinical Symptoms and Rating Scales. W. MAIER and P. BECH... '"... " Methodological Problems in Assessing Quality of Life as Outcome in Psychopharmacology: A Multiaxial Approach. P. BECH. With I Figure
8 x Contents Ascertainment of Side Effects in Psychopharmacologic Clinical Trials. J. LEVINE Selection Criteria for Drug Trials Diagnoses as Selection Criteria in Drug Trials. R. BULLER and W. MAIER Functional Classification and Response to Psychotropic Drugs. O. BENKERT Appendix National and International Guidelines for the Conduct of Clinical Trials of Psychotropic Drugs. B. MULLER-OERLINGHAUSEN Subject Index
9 List of Contributors You will find the addresses at the beginning of the respective contribution. Barnes, T.R.E. 26 Bech, P. 105, 121 Benkert, o. 155 Berger, M. 56 Buller, R. 139 Crook, T.H. 37 Helmchen, H. 82 Hirsch, S.R. 26 Hohagen, F. 56 Johnson, B.A. 37 Larrabee, G.J. 37 Lavori, P. 91 Levine, J. 130 Maier, W. 105, 139 Miiller-Oerlinghausen, B. 167 Paykel, E.S. 73 Rickels, K. 3
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