Osteoporosis: FDA Finalizes Nonclinical Development Guidance
Posted 14 August 2019 | By
The US Food and Drug Administration (FDA) on Wednesday finalized guidance for drugmakers on designing long-term nonclinical bone quality studies for drugs and biologics to treat osteoporosis.
“In addition to the pharmacology and toxicology studies required to support development of a new drug or biologic, long-term nonclinical studies, including bone-specific pharmacologic and toxicologic endpoints to evaluate the effects on bone quality, need to be conducted in appropriate animal models,” FDA writes.
FDA says such studies are necessary due to concerns over long-term adverse effects of drugs on bone quality and because “there are no validated and reliable methods for the noninvasive assessment of bone quality in humans.”
The eight-page guidance finalizes a draft version
issued for comment in June 2016 and includes minor changes to the agency’s recommendations for conducting bone quality studies as well as some reorganized sections.
The final guidance retains the draft version’s recommendation that bone quality studies should generally be conducted in two animal species for drugs. For biologics, FDA says that “it may be appropriate to conduct bone quality studies as well as toxicology studies in a single pharmacologically responsive animal species.”
For postmenopausal osteoporosis, both the final and draft guidances recommend bone quality studies be conducted in ovariectomized rats and a larger ovariectomized nonrodent species, such as nonhuman primates, sheep, pigs or dogs.
For already approved osteoporosis treatments, the final guidance clarifies that for combination drug treatments, additional animal studies may be needed “depending on the level of scientific concern,” while the draft version does not specifically mention drug combinations.
The final guidance also lowers the number of doses that should be investigated in the bone quality studies from three to two—a dose that induces an optimal pharmacological effect and a high dose—making the low dose recommended in the draft guidance optional.
The recommended treatment duration for the bone quality studies has also been changed from “equivalent to approximately three years of human exposure” to a recommendation that the sponsor “determine the treatment duration based on the intended clinical treatment duration and the bone remodeling cycle duration in the species studied.” However, the final guidance still provides study durations for various species that would be equivalent to three years of human exposure.
Additionally, the final guidance recommends that sponsors consider a nonrodent species aside from monkeys as the second species in their bone quality studies and makes specific recommendations for the group sizes of rats and larger animals used in the studies.