1. U.S. Guidance for the Development of Drugs for Osteoporosis: Rationale, Durability and Evolution Henry Bone, M.D. Michigan Bone & Mineral Clinic Detroit, Michigan

2. Osteoporosis: A spectrum of disorders Chronic Osteoporoses  Postmenopausal osteoporosis –enormous numbers at risk –wide spectrum of severity  Chronic glucocorticosteroid exposure –risk additive with underlying disease  “Male Osteoporosis”

3. Osteoporosis: A spectrum of disorders Accelerated osteoporoses Immobilization –neurological, other Transplantation –renal, liver, heart, lung Recent fracture

4. Development Guidelines / Pathways US / FDA WHO working group EU / CPMP There are many similarities Main differences involve the role of BMD vs direct assessment of the effect on fracture rate for initial registration.

5. Experience Leading to US Guidelines II Revision 1993-94 Laws of physics not revoked, but Drugs that apparently increased mass but did not decrease fracture rates Preclinical abnormalities: F, EHDP Failed trial: sCT Issues: mass vs strength, meaning of “quality”

6. Principles of Current US Guidelines Robust preclincal testing can identify drugs with harmful effects on bone The above statement is not “proven” Drugs which do not harm “quality” may be approved based on BMD provided there is confirmatory trend in ongoing fracture studies, which must be completed Drugs with possible adverse effects on quality must be proven to reduce fx rate

7. Preclinical Evaluation: General Considerations Model systems have several purposes: –model the disease and response to tx –detect specific adverse effects –model specific pharmacokinetic and/or pharmacodynamic phenomena Preclinical testing is generally reliable, –but results need clinical confirmation

8. Preclinical Evaluation of Anti- Osteoporotic Agents Complementary to toxicology Studies of bone quality: architecture, mass and strength More limited requirements for E Primary objective: demonstrate that long-term treatment will not lead to deleterious effects

9. Rationale for 3 year observation BMD –Reequilibration? (SQ sCT) Fx –Accrual of adverse effect? (EHDP)

10. “Trust, but verify” Confirm qualitative effects in humans by evaluating fracture rate –Vertebral, non-vertebral –Supports specific claims Must this be repeated for each indication? What statistical tests should be applied for confirmation of effect at additional sites

11. Osteoporosis Guidelines: WHO, FDA and CPMP Similar preclinical testing recommendations Similar phase II requirements –Biochemical markers for mechanistic evaluation, dose findings –One year BMD for phase IIb

12. Osteoporosis Guidelines: WHO, FDA and CPMP Main differences: WHO would register a drug based on BMD without fracture trial, if it has a satisfactory preclinical profile FDA requires favorable trend in fracture trial when allowing initial registration based on BMD, for drugs with good preclinical data CPMP requires definitive anti-fracture efficacy for initial registration

13. Possible endpoints for registration trials Preclinical: no bone quality problems at 5X dose –BMD only –BMD primary, with supportive fx data –Fx only Preclinical: concerns about quality at high dose –Fx endpoint primary –Quit –???

14. Context of the Guidance--1994 Fewer therapeutic options, none with rigorously established antifracture efficacy Experience with drugs that induced quality problems Limited experience with well-validated therapeutic options

15. Changes in the Scientific Context More therapeutic experience with –Aminobisphosphonates –SERM (one registered, several failed) –Estrogen (WHI) –PTH (pending) Technological advances More experience relating outcomes to preclinical and clinical measurements Better quantified risk estimates for trials

16. Interaction of FDA and CPMP guidances Alendronate and raloxifene registered per US guidance Subsequent development programs were carried out to meet stricter CPMP requirements

17. Changes in the Clinical Context Several drugs now available, 30-50% RRR Fracture rate reduction: widely accepted clinical outcome measure, but Prevailing “standard” of care: no Rx for most osteoporotic women –Less than 10%, even after hip fracture –Some use of Ca and vitamin D, still a minority

18. Emerging Issues in Osteoporosis Guidance Develop improved therapies –Novel mechanisms, especially anabolic –Alternative regimens (compliance) –Combinations with complementary mechanisms Limit risk to participants Keep development time and costs within range that does not preclude drug development

19. What about “placebo” controlled trials with fracture endpoints? “Placebo” is a misnomer –Trials always include background Ca and vitamin D, compare active vs. PBO tablet –Before effective therapies, high risk subjects included Current view: such trials are now considered acceptable in patients with relatively low fracture risk, but not in high risk patients (e.g. with multiple or recent fractures) –Implications for trial design

20. In the present context, can we reevaluate endpoints? What do we need to know? And when? –What do regulators need to know to register a drug (safe and effective)? –What do physicians need to know to make good clinical decisions? FDA regulates both registration and subsequent claims If less is required at registration, more may be needed later

21. Specific points Preclinical testing requirements— relationship to phase III / registration Clinical trial endpoints –Registration –Outcomes Analysis / inference –Statistics –Multiple specific indications

24. Biochemical markers of bone remodeling Emerging role of biochemical markers of bone remodeling: short response time, predictive of clinical effect No direct structural relationship between markers and strength Markers are indicative of bone remodeling activity, drug effect Indicate changes in remodeling space Relation to efficacy for antiresorptives only

25. Purpose of models –Models validated for adverse effects Elucidate mechanisms Demonstrate efficacy Detect adverse effects

26. Preclinical Studies for Osteoporosis -- Bone Quality Mass Architecture Strength

27. Preclinical Studies in Osteoporosis --Animal Systems Two Species –Ovariectomized rat Larger, remodeling species –usually primates –justify also refers to GCS tx’d & castrated males

28. Reflects clinical indication –prevention vs. treatment –early vs. late post-ovx Treatment schedule –continuous vs. intermittent Dosage - 1x to 5x Duration –comparable to 4 yrs of human exposure Preclinical Studies in Osteoporosis --Study Design

29. Preclinical Endpoints for Testing of Anti-Osteoporotic Agents Bone mass/density: –ash weight, radiologic methods Histology, histomorphometry Biochemical markers of turnover Biomechanical testing: –bending, torsion on long bones –compression of vertebrae

30. Biochemical markers of resorption & formation Light microscopy, polarized light, tetracycline- labelled histomorphometry Long Bones & Vertebrae –Histomorphometric analysis –Bone density / mass (ASU) –Biochemical testing of strength Relate to clinical efficacy measurements Preclinical Studies in Osteoporosis --Measurement

31. Experience with Preclinical Identification of Harmful Drug Effects on Bone Quality EHDP  mineralization defect F  histologic abnormalities decreased strength No examples of bone-toxic drugs identified by preclinical studies