GUIDELINES FOR PRECLINICAL AND CLINICAL EVALUATION
OF
AGENTS USED IN THE PREVENTION OR TREATMENT
OF
POSTMENOPAUSAL OSTEOPOROSIS

April, 1994

The FDA published Good Guidance Practices in February 1997.
This guidance was developed and issued prior to that date.

Division of Metabolic and Endocrine Drug Products
Food and Drug Administration
5600 Fishers Lane, HFD-510
Rockville, Maryland 20857-1706
(301)827-6430

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GUIDELINES FOR PRECLINICAL AND CLINICAL EVALUATION
OF AGENTS USED IN THE PREVENTION OR TREATMENT
OF POSTMENOPAUSAL OSTEOPOROSIS

Table of Contents
Page
Preclinical Evaluation
I.
II.
III.
IV.
V.
VI.
VII.
VIII.

Introduction
Study Design
Animal Models
Biochemical Markers of Bone Turnover
Bone Mass/Density Measurement
Analysis of Bone Architecture/Histology
Biomechanical Testing of Bone Strength
Regulatory Aspects

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Clinical Evaluation
I. Introduction
II. Clinical Studies
III. Study Duration and Assessment of Efficacy
IV. Procedure and Evaluation
V. Statistical Consideration
VI. Safety Testing
VII. Guide to FDA Action on NDA for Osteoporosis
VIII. Issues Related to Testing of
Combined Drug Regimens
IX. Research Priorities in
Postmenopausal Osteoporosis
X. References

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GUIDELINES FOR PRECLINICAL AND CLINICAL EVALUATION OF AGENTS USED
IN THE PREVENTION OR TREATMENT OF POSTMENOPAUSAL OSTEOPOROSIS
Preclinical Evaluation
I. Introduction
In addition to the toxicity studies required for all new drugs
(see CFR 312.23(8)), preclinical studies of bone quality should be performed for drugs to be used in the prevention and intervention of osteoporosis. For these guidelines, bone quality is considered to be comprised of the architecture, mass and strength of bone. These studies are warranted by instances in which bone density was not positively correlated with architecture and strength. Non-invasive techniques for assessing bone strength clinically (such as ultrasound) have not been adequately validated, but animal studies provide an opportunity to directly examine bone mass, architecture and strength. Thus, the primary objective of these studies is to demonstrate that long term treatment with a specific agent will not lead to deleterious effects on bone quality.
The proposed animal studies will permit early identification of drugs that result in abnormal architecture or in production of bone in which strength is not positively correlated with density and architecture. It may be possible to identify doses that control excessive bone resorption without suppressing osteoblast activity. These preclinical studies of bone quality might demonstrate efficacy in animals, but clinical efficacy must still be established.
Because no single animal species duplicates all the characteristics of human osteoporosis, it is felt that an examination of bone quality in two species is necessary to adequately investigate the effectiveness and safety of drugs for this indication. One study should be conducted in the ovariectomized rat model and the second in a non-rodent model
(i.e., larger, remodeling species) which will be left to the discretion of the sponsor although there is evidence that the dog may not be a good model1. Parameters to be monitored in these studies include biochemical markers of bone resorption and formation, histomorphometric analysis of bone architecture, measurement of bone density and biomechanical testing of bone strength. Histomorphometric, densitometric and biomechanical analyses should be performed on both long bones (femur and tibia) and lumbar vertebral bodies. Whenever possible, the parameters and techniques that will be used to demonstrate clinical efficacy should also be pursued in the preclinical studies. Further recommendations on these studies are detailed in the subsequent sections. 3
II. Study Design
Time of initiation of treatment in preclinical studies should be reflective of the clinical indication. Specifically, time of initiation of treatment will be different