title: The use of placebo-controlled and non-inferiority trials for the evaluation of new drugs in the treatment of postmenopausal osteoporosis.
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 European 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 postmenopausal 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.
authors.affiliation: INSERM Research Unit 403 and Claude Bernard University of Lyon, France. delmas@lyon151.inserm.fr
authors.forename: P D
authors.initials: PD
authors.lastname: Delmas
authors.forename: G
authors.initials: G
authors.lastname: Calvo
authors.forename: M
authors.initials: M
authors.lastname: Boers
authors.forename: E
authors.initials: E
authors.lastname: Abadie
authors.forename: B
authors.initials: B
authors.lastname: Avouac
authors.forename: A
authors.initials: A
authors.lastname: Kahan
authors.forename: J M
authors.initials: JM
authors.lastname: Kaufman
authors.forename: A
authors.initials: A
authors.lastname: Laslop
authors.forename: J F
authors.initials: JF
authors.lastname: Lekkerkerker
authors.forename: P
authors.initials: P
authors.lastname: Nilsson
authors.forename: B
authors.initials: B
authors.lastname: Van Zwieten-Boot
authors.forename: G
authors.initials: G
authors.lastname: Kreutz
authors.forename: J Y
authors.initials: JY
authors.lastname: Reginster
mesh_terms: D000368:Aged; D018849:Controlled Clinical Trials as Topic / Q000379:methods*; D026690:Ethics, Clinical; D005062:European Union; D005260:Female; D006801:Humans; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy*; D015990:Placebo Effect; D012107:Research Design