Expert consensus recommendations on the use of randomized clinical trials for drug approval in psychiatry- comparing trial designs.

The use of randomized clinical trials, in particular placebo-controlled trials, for drug approval, is the subject of long-standing debate in the scientific community and beyond. This study offers consensus recommendations from clinical and academic experts to guide the selection of clinical trial design in psychiatry. Forty-one highly cited clinical psychiatrists and/or researchers participated in a Delphi survey. Consensus statements were developed based on the findings of a published, peer-reviewed systematic review. Participants evaluated statements in two survey rounds, following the Delphi method. The expert panel achieved consensus on 7 of 21 recommendations regarding the use of randomized clinical trials. The endorsed recommendations were: (i) Results from placebo-controlled trials are the most reliable and (ii) are necessary despite the growing placebo-effect; (iii) it is ethical to enroll patients in placebo-arms when established treatment is available, if there is no evidence of increased health risk; (iv) There is a need to approve new drugs with the same efficacy as existing treatments, but with different side-effect profiles; (v) Non-inferiority trials incur an increased risk of approving ineffective medications; (vi) The risk of approving an ineffective drug justifies trial designs that incur higher costs, and (vii) superiority trials incur the risk of rejecting potentially efficacious treatments. The endorsed recommendations inform the choice of trial-design appropriate for approval of psychopharmacological drugs. The recommendations strongly support the use of randomized clinical trials in general, and the use of placebo-controlled trials in particular.
Competing Interests: Declaration of Competing Interest Guy M. Goodwin is a NIHR Emeritus Senior Investigator, holds shares in P1vital and P1Vital products and has served as consultant, advisor or CME speaker in the last 3 years for Beckley Psytech, Clerkenwell Health, Compass pathways, Evapharma, Janssen, Lundbeck, Medscape, Novartis, P1Vital, Sage, Servier. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Michael Berk is supported by a NHMRC Senior Principal Research Fellowship (1156072). MB has received Grant/Research Support from the NIH, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley Medical Research Foundation, Medical Benefits Fund, National Health and Medical Research Council, Medical Research Futures Fund, Beyond Blue, Rotary Health, A2 milk company, Meat and Livestock Board, Woolworths, Avant and the Harry Windsor Foundation, has been a speaker for Abbot, Astra Zeneca, Janssen and Janssen, Lundbeck and Merck and served as a consultant to Allergan, Astra Zeneca, Bioadvantex, Bionomics, Collaborative Medicinal Development, Janssen and Janssen, Lundbeck Merck, Pfizer and Servier – all unrelated to this work. Andreas Meyer-Lindenberg has received consultant fees from: Boehringer Ingelheim, Elsevier, Brainsway, Lundbeck Int. Neuroscience Foundation, Lundbeck A/S, The Wolfson Foundation, Bloomfield Holding Ltd, Shanghai Research Center for Brain Science, Thieme Verlag, Sage Therapeutics, v Behring Röntgen Stiftung, Fondation FondaMental, Janssen-Cilag GmbH, MedinCell, Brain Mind Institute, Agence Nationale de la Recherche, CISSN (Catania Internat. Summer School of Neuroscience), Daimler und Benz Stiftung, American Association for the Advancement of Science, Servier International. Additionally, he has received speaker fees from: Italian Society of Biological Psychiatry, Merz-Stiftung, Forum Werkstatt Karlsruhe, Lundbeck SAS France, BAG Psychiatrie Oberbayern, Klinik für Psychiatrie und Psychotherapie Ingolstadt, med Update GmbH, Society of Biological Psychiatry, Siemens Healthineers, Biotest AG -All unrelated to this work. Terence A. Ketter has been a consultant to Otsuka Pharmaceuticals, Sunovion Pharmaceuticals, Abbvie, and Alkermes. Joseph Goldberg has been a consultant to BioXCel, Otsuka, Sage Pharmaceuticals, Sunovion, and WebMD, and served on the speaker boards for Allergan, Intracellular Therapies, and Sunovion. Rif S. El-Mallakh is on the speaker bureau of Alkermes, Eisai, Indivior, Intra-Cellular Therapeutics, Janssen, Lundbeck, Noven, Otsuka, Sunonvion, and Teva. Lakshmi N Yatham has been on speaker/advisory boards for, or has received research grants from Abbvie, Alkermes, Allergan, CANMAT, CIHR, DSP, Merck, and Sanofi Rasmus W. Licht has within the preceding three years served an advisory board of Janssen Cilag and Sagw, and received speaker honorarium from Astra-Zeneca, Jannsen-Cilag, Servier and Lundbeck Allan H. Young has been employed by King's College London; Honorary Consultant SLaM (NHS UK). Young has participated in paid lectures and advisory boards for the following companies with drugs used in affective and related disorders: Astrazenaca, Eli Lilly, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allegan, Bionomics, Sumitomo Dainippon Pharma, COMPASS Allan H. Young's independent research funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health.Consultant to Johnson & Johnson and Livanova. Received honoraria for attending advisory boards and presenting talks at meetings organized by LivaNova. Prof. Alessandro Serretti is or has been consultant/speaker for: Abbott, Abbvie, Angelini, Astra Zeneca, Clinical Data, Bo- heringer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi, Servier. Ayşegül Yildiz has nothing to declare. Jean Michel Azorin has received honoraria or research or educational conference grants from Lundbeck and Otsuka. Othman Sentissi has received advisory board honoraria or research or educational conference from Otsuka, Lilly, Lundbeck, Sandoz, Janssen and Sunovion on an institutional account for research and teaching. Prof. Gordon Parker has received lecture fees and board member honoraria from Otsuka, Servier and Lundbeck. Dr. David Bond has received consulting fees and/or research grants from Alkermes, Myriad Genetics, the National Institutes of Health, the University of Minnesota Department of Psychiatry and Behavioral Sciences, and the University of Minnesota Foundation. Prof. Giulio Perugi has received grant/research support from Eli Lilly & Co.; is on the speaker/advisory board of Sanofi-Aventis, Bristol-Myers Squibb, AstraZeneca, Eli Lilly & Co., Jannsen-Cilag, and Lundbeck; and has acted as consultant of AstraZeneca, Eli Lilly & Co., and Lundbeck. Prof. Eduard Vieta has received grants and served as consultant, advisor or CME speaker for the following entities: AB- Biotics, Abbott, Allergan, Angelini, Dainippon Sumitomo Pharma, Galenica, Janssen, Lundbeck, Novartis, Otsuka, Sage, Sanofi-Aventis, and Takeda. Dina Popovic has served as a speaker and/or medical writer and/or consultant and/or has participated in advisory boards for Bristol-Myers Squibb, Dexel, Merck Sharp & Dohme, Janssen-Cilag, Lundbeck, Ferrer, and Forum Pharmaceuticals. None of the remaining authors have conflicts of interest to declare.
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