Editorial The Use of Placebo-Controlled and Non-inferiority Trials for the Evaluation of New Drugs in the Treatment of Postmenopausal Osteoporosis P. D. Delmas 1 , G. Calvo 2 , M. Boers 3 , E. Abadie 4 , B. Avouac 5 , A. Kahan 6 , J. M. Kaufman 7 , A. Laslop 8 , J. F. Lekkerkerker 9 , P. Nilsson 10 , B. Van Zwieten-Boot 11 , G. Kreutz 12 and J. Y. Reginster 13 on behalf of the Group for the Respect of Ethics and Excellence in Science (GREES) 1 INSERM Research Unit 403 and Claude Bernard University of Lyon, France; 2 Department of Clinical Pharmacology, Santa Creu i Sant Pau Hospital, Autonomous University of Barcelona, Spain; 3 Department of Clinical Epidemiology & Biostatistics, VU University Medical Center, Amsterdam, The Netherlands; 4 Agence Franc ¸aise du Me ´dicament, Saint-Denis, France; 5 Service de Rhumatologie, Ho ˆ pital Henri Mondor, Cre ´teil, France; 6 Universite ´ de Paris V, AP-HP, Ho ˆ pital Cochin, Paris, France; 7 Department of Endocrinology and Unit for Osteoporosis and Metabolic Bone Diseases, Ghent University Hospital, Belgium; 8 Department of Pharmacology, University of Innsbruck, Austria; 9 Medicines Evaluation Board, The Hague, The Netherlands; 10 Medical Product Agency, Uppsala, Sweden; 11 Medicines Evaluation Board, The Hague, The Netherlands; 12 BfArM ARM, Bonn, Germany; and 13 Department of Epidemiology and Public Health, University of Lie `ge and World Health Organization Collaborating Center for Public Health Aspects of Rheumatic Disease, Lie `ge, Belgium Abstract. Registration of new agents for the treatment of postmenopausal osteoporosis has been based over the past few years on placebo-controlled phase III trials with the incidence of patients with new vertebral/nonvertebral fractures as the most usual primary endpoint. The use of a placebo in diseases where an active treatment is available has been a matter of debate following the update of the Declaration of Helsinki by the World Medical Association which questioned this trial design. Current regulatory recommendations within the Eur- opean Union suggest that placebo-controlled trials are still the best option when assessing the efficacy and safety of new drugs intended for the treatment of postmenopausal osteoporosis. This suggestion seems to be in apparent contradiction with the current content of the Declaration of Helsinki. This paper addresses the ethics and feasibility of placebo-controlled trials in the treatment of postmenopausal osteoporosis, in the light of available therapeutic options, and discusses possible alternative approaches in those patients where placebo treatment could be deemed to be unethical. It is concluded that placebo-controlled trials remain the most efficient design to establish the efficacy and safety of a new agent for the treatment of postmeno- pausal osteoporosis. Such trials are feasible and ethically acceptable in patients with osteoporosis but without prevalent vertebral fractures. Conversely, in patients with prevalent vertebral fractures, placebo-controlled trials are ethically questionable and non-inferiority trials are more appropriate. A relative margin of non- inferiority of 20–30% is suggested, to be discussed on a case by case basis. Keywords: Clinical trial; Drug registration; Osteo- porosis; Placebo Introduction The question of whether a new entity should be developed with placebo or comparator control has been a matter of debate, especially following the publication at the end of 2000 of the update of the Declaration of Helsinki, ‘Ethical Principles for Medical Research Osteoporos Int (2002) 13:1–5 ß 2002 International Osteoporosis Foundation and National Osteoporosis Foundation Osteoporosis International Correspondence and offprint requests to: Prof. P. D. Delmas, Pavillon F, Ho ˆ pital Edouard Herriot, F-69437 Lyon cedex 3, France. Tel: +33 4 72 11 74 84. Fax: +33 4 72 11 74 83. e-mail: delmas@lyon151.inserm.fr