On June 13, FDA released a new pharmacology/toxicology guidance providing guidance on nonclinical studies to support the approval of drugs intended for the treatment of osteoporosis. This guidance outlines long-term nonclinical pharmacology studies (i.e., bone quality studies) that should be conducted in addition to the standard nonclinical pharmacology and toxicology studies required for all new drugs (as laid out in 21 CFR 312.23(a)(8)).
In the background of the guidance, FDA specifies that the phrase ‘bone quality’ refers to those structural and material properties of bone that determine its biomechanical behavior in ways that are not accounted for by bone quantity or mass. FDA explains that these bone quality studies are warranted because of concerns about long-terms adverse effects of pharmaceutical agents on the quality of bone and because there are no validated and reliable methods for the noninvasive assessment of bone quality in humans. While FDA recognizes that bone quality cannot be easily assessed directly, the Agency indicates that these nonclinical studies will allow for researchers to collect indirect information about bone quality through other metrics such as bone strength (which is determined by both bone mass and bone quality).
FDA indicates that bone quality studies should generally be conducted in two different animal species, and advises on the choice of species for postmenopausal osteoporosis models (e.g., one study in ovariectomized rats and another study in a larger ovariectomized nonrodent such as nonhuman primate, sheep, pig, or dog). For other forms of osteoporosis, FDA notes that appropriate animal models and transgenic animal models may provide relevant information. FDA also provides recommendations on study design including specific information on dose selection (high dose, low dose, and optimally effective dose) and study duration (should consist of a number of remodeling cycles equivalent to approximately 3 years of human exposure). Finally, FDA provides recommendations on evaluations of bone turnover, bone mass and density, bone structure and architecture, and bone strength.
FDA notes that biologics such as recombinant proteins and monoclonal antibodies (referred to as biopharmaceuticals) may not need to adhere to the aforementioned recommendations since choosing an appropriate animal model can be difficult if the target receptor/antigen is not present in common animal tests. As a result, FDA explains that a study in a single responsive animal species may be sufficient, and if no relevant test species exist, alternative models (e.g., the use of an analogous drug against the target or the use of a transgenic model) can be considered.
FDA also provides separate specific recommendations for anabolic agents, noting their potential carcinogenicity. FDA indicates that previous nonclinical studies have shown bone tumor growth in rats and mice dosed with parathyroid hormone (PTH) or parathyroid hormone-related peptide (PTHrP) drugs. Consequently, FDA specifies that studies to evaluate carcinogenic potential generally should be conducted with PTH drugs developed for the treatment of osteoporosis.