clinical trial; drug registration; osteoporosis; placebo
Abstract :
[en] 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.
Disciplines :
Endocrinology, metabolism & nutrition
Author, co-author :
Delmas, P. D.
Calvo, Gisèle ; Centre Hospitalier Universitaire de Liège - CHU > Imagerie médicale
Boers, M.
Abadie, Eric ; Université de Liège - ULiège > Epidémiologie et santé publique
Avouac, Bernard ; Université de Liège - ULiège > Unité d'exploration du métabolisme osseux
Kahan, A.
Kaufman, J. M.
Laslop, A.
Lekkerkerker, J. F.
Nilsson, P.
Van Zwieten-Boot, B.
Kreutz, G.
Reginster, Jean-Yves ; Université de Liège - ULiège > Département des sciences de la santé publique > Epidémiologie et santé publique
(1997) Recommendations guiding physicians in biomedical research involving human subjects. JAMA 227:925-926.
(2000) Ethical principles for medical research involving human subjects. 52nd WMA General Assembly, Edinburgh, Scotland, October; .
The use of placebo controls in clinical trials, Report 2-A-1996. Chicago: American Medical Association; 1996.
Grof P., Akhter M.I., Campbell M., Gottfries C.G., Khan I., Lapierre Y.D. Clinical evaluation of psychotropic drugs for psychiatric disorders: Principle and proposed guidelines. WHO expert series on biological psychiatry , Seattle: Hogrefe & Huber; 1993, 2:28-29.
International ethical guidelines for biomedical research involving human subjects, Geneva: Council for International Organizations of Medical Sciences; 1993.
Simon R. (2000) Editorial: Are placebo-controlled clinical trials ethical or needed when alternative treatment exists?. Ann Intern Med 133:474-475.
Temple R., Ellenberg S.S. (2000) Placebo-controlled trials and active-control trials in the evaluation of new treatments. I. Ethical and scientific issues. Ann Intern Med 133:455-463.
Ellenberg S.S., Temple R.T. (2000) Placebo-controlled trials and active-control trials in the evaluation of new treatments. II. Practical issues and specific cases. Ann Intern Med 133:464-470.
Note for guidance on postmenopausal osteoporosis in women2001. http://www.emea.eu.int/pdfs/human/ewp/055295en.pdf
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH harmonised tripartite guideline: statistical principles for clinical trials (ICH-E9). http://www.ifpma.org/pdfifpma/e9.pdf
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH harmonised tripartite guideline: Choice of the control group and related issues in clinical trials (ICH-E10). http://www.ifpma.org/pdfifpma/e10step4.pdf
Jones B., Jarvis P., Lewis J.A., Ebbutt A.F. (1996) Trials to assess equivalence: The importance of rigorous methods. BMJ 313:36-39.
Points to consider on switching between superiority and non-inferiority. http://www.emea.eu.int/pdfs/human/ewp/048299en.pdf
Lublin F.D., Reingold S.C. (2001) Placebo-controlled trials in multiple sclerosis: Ethical considerations. Ann Neurol 49:667-681.
Black D.M., Cummings S.R., Karpf D.B. (1996) Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet 348:1535-1541.
Cummings S.R., Black D.M., Thompson D.E. (1998) Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: Results from the Fracture Intervention trial. JAMA 280:2077-2082.
Ettinger B., Black D.M., Mitlak B.H. (1999) Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: Results from a 3-year randomized clinical trial. JAMA , Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators; 282:637-645.
Harris S.T., Watts N.B., Genant H.K. (1999) Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: A randomized controlled trial. JAMA , Vertebral Efficacy with Risedronate Therapy (VERT) Study Group; 282:1344-1352.
Reginster J., Minne H.W., Sorensen O.H. (2000) Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Osteoporos Int , Vertebral Efficacy with Risedronate Therapy (VERT) Study Group; 11:83-91.
Neer R.M., Arnaud C.D., Zanchetta J.R. (2001) Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 344:1434-1441.
McClung M.R., Geusens P., Miller P.D. (2001) Effect of risedronate on the risk of hip fracture in elderly women. N Engl J Med , Hip Intervention Program Study Group; 344:333-340.
Christie B. (2000) Doctors revise Declaration of Helsinki. BMJ 321:913.
Chapuy M.C., Arlot M.E., Delmas P.D., Meunier P.J. (1994) Effect of calcium and cholecalciferol treatment of three years on hip fracture in elderly women. BMJ 308:1081-1082.
Lindsay R., Silverman S.L., Cooper C., Hanley D.A., Barton I. (2001) Risk of new vertebral fracture in the year following a fracture. JAMA 285:320-323.