CONTRIBUTION OF PRECLINICAL STUDIES TO EVALUATION OF 临床前研究的贡献评价.pptVIP

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CONTRIBUTION OF PRECLINICAL STUDIES TO EVALUATION OF 临床前研究的贡献评价.ppt

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CONTRIBUTION OF PRECLINICAL STUDIES TO EVALUATION OF 临床前研究的贡献评价

CONTRIBUTION OF PRECLINICAL STUDIES TO EVALUATION OF OSTEOPOROSIS THERAPY Gideon A Rodan MD PhD Merck Research Laboratories Bone Biology and Osteoporosis Research PRECLINICAL INFORMATION Hypothesis: Preclinical studies can reduce the burden of proof required of clinical trials, by providing information on Safety (general and bone) Efficacy Mechanism (pharmacological activity and adverse events) Historical Perspective and Current Osteoporosis Guidelines Pre 1994: Increased BMD in 2 year PBO-controlled trials plus preclinical evidence for bone safety/quality Reasons for change: No fracture reduction during third year with etidronate treatment, hence three year studies No fracture reduction during fluoride treatment, in spite of increased BMD, hence fracture endpoint ETIDRONATE PRECLINICAL STUDIES Spontaneous fractures in dogs (Flora et al) Impaired fracture healing in dogs (Nunnemaker et al) Narrow efficacy/safety window (MRL study) FLUORIDE PRECLINICAL STUDIES Bone strength increase is not commensurate with bone mass increases (Mosekilde et al. CTI 1987, 40:318-322) Abnormal mineralization by x-ray scattering (Fratzl et al JBMR 1994, 9:1541-1549) MRL study (Lafage et al, JCI 1995, 95:2127-2133) Correlation of Vertebral Bone Mass and Bone Strength In Alendronate Treated Animals Comparison of Alendronate and NaF Effects on Bone Strength vs. Bone Mass Bone Strength decreases with increased NaF content PRECLINICAL MODELS FOR BONE SAFETYCONCLUSIONS Bone measurements (histology and strength) in animal models at multiples (5x?) of the therapeutic dose detected deleterious effects of etidronate and fluoride, and could be sensitive enough to evaluate the bone safety of prospective OP therapies. Recommendation Use bones from long term toxicology studies to evaluate bone safety (histology and strength). PRECLINICAL MODELS FOR EFFICACY Estrogen-deficiency bone loss (cancellouscortical) occurs in most mammals including humans, rodents, primates and other species (in