Preclinical Study Requirements

In addition to the normal toxicological and pharmacological studies required, there is a specific requirement for pharmacology studies in two different recognized animal models of osteoporosis. One of these studies should be conducted in an oophorectomized rat model and be of 12 months' duration. A second study should be in a large-animal model that shows full skeletal remodeling (sheep, pigs, and primates are given as good examples, but the validity of dog models is questioned). The large-animal study should be of 16 months' duration. The purpose of these studies is to demonstrate that the new chemical entity (NCE) tested does not have deleterious effects on bone quality, despite positive effects on bone mass. This requirement reflects a concern initially raised about fluoride, which increases BMD but can reduce bone strength. Reflecting the concerns regarding bone quality, these two pharmacology studies must include evaluation of bone quality as endpoints. This can be achieved, showing bone matrix structure (lamellar or woven), trabecular architecture, and bone mechanical strength are maintained or improved, as well as bone mass increased. It may be possible to argue exception from these requirements if the drug being developed cannot be used in rats and/or larger species, as could be the case for a monoclonal antibody specific for a human protein. Use of surrogate markers of bone remodeling is required to confirm pharmacologic actions of NCEs throughout the duration of these studies.

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