Is it ethical to conduct placebo-controlled clinical trials in the development of new agents for osteoporosis? An industry perspective.

To represent industry on the topic of this conference, position papers were obtained from six pharmaceutical and biotechnology companies. Despite their holding a wide range of positions in the market with regard to prevention and treatment of osteoporosis, all companies were unanimous in their concerns about the ability to conduct randomized placebo-controlled clinical trials (PCTs) in the future. The clinical research environment contains conflicting directives. Regulatory agencies strongly prefer (even insist on) PCTs as a requirement for drug approval, while many physicians, human studies institutional review boards, and informed patients believe that it is no longer ethical to place osteoporotic patients on placebo because effective therapies are now available. PCTs offer the best means of calibrating the absolute efficacy of a new agent and identifying its side effects against a "neutral" background. Are comparison-controlled clinical trials (CCTs) using an approved drug the answer? No. Examples are given that illustrate that such trials require very large numbers of patients to show "non-inferiority" (approximately 15,000-20,000) or "superiority" (approximately 30,000) compared with an existing approved therapy. Such studies are not only impractical, but also accumulate a greater number of fractures during the course of clinical research in both the new treatment and control (active comparator) groups than would occur in PCTs. Total adverse experiences and exposure of patients to investigational agents is considerably greater when CCTs rather than PCTs are used. Based on this analysis, industry recommends that regulatory approval of new agents for osteoporosis be based on (1) conduct of PCTs in patients at low risk for fracture (e.g., T-score < -2.5 and no previous osteoporotic fracture); (2) use of bone mineral density as an end-point for the indication "to preserve or improve bone mass"; (3) a 2-year, rather than 3-year, trial period; (4) demonstration of no adverse effect on bone quality preclinically; (5) extrapolation of clinical trial results to higher risk patients; (6) an option for the sponsor to perform additional fracture end-point studies postapproval to obtain an indication for "treatment to reduce the risk of fractures specifically in the spine, hip, or both"; and (7) the option to file for a "prevention" claim before a "treatment" claim.