U.S. Guidance for the Development of Drugs for Osteoporosis: Rationale, Durability and Evolution

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. 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 ??? Possible endpoints for registration trials

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. Preclinical Studies in Osteoporosis --Study Design • 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

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. Preclinical Studies in Osteoporosis --Measurement • 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

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