1. FDA’s Osteoporosis Guidance Center for Drug Evaluation and Research Division of Metabolic and Endocrine Drugs Eric Colman, MD September 25, 2002

2. Topics of Discussion Regulatory history –Estrogens –Non-estrogens Development of the Osteoporosis Guidance –1979 –1985 –1994

3. Abbreviations Postmenopausal osteoporosis = PMO Bone mineral density = BMD

4. Regulatory History of Estrogens 1942 - FDA approved conjugated estrogens for menopausal symptoms 1972 - estrogen “probably effective” for selected cases of osteoporosis 1990 - “The mainstays of prevention and management of osteoporosis are estrogen and calcium.” 2000 - “Prevention of osteoporosis.”

5. Estrogens and Osteoporosis Estrogens increase BMD WHI data indicate estrogen + progestin reduces fracture risk Risks outweigh benefits? Estrogens currently approved for prevention, but not treatment, of PMO

6. Regulatory History of Non-Estrogens Calcitonin Fluoride Bisphosphonates SERM

7. History of Non-Estrogens Injectable calcitonin approved in 1984 –Total body calcium –Phase 4 fracture study Fluoride –  BMD -  fracture risk Etidronate 1991 –Potential for osteomalacia in preclinical studies –Loss of fracture efficacy in 3rd year? –BMD - fracture discrepancy??

8. History of Non-Estrogens Calcitonin nasal spray approved in 1995 –Treatment of PMO to prevent the progressive loss of bone mass –No definitive fracture data Alendronate 1995 –Treatment of PMO (fracture data) –Prevention of PMO (BMD + fracture) –  BMD -  vertebral fracture risk

9. History of Non-Estrogens Raloxifene - 1997 –prevention of PMO (BMD) –treatment of PMO (fracture) –  BMD -  vertebral fracture risk Risedronate - 1999 –treatment of PMO (fracture) –prevention of PMO (BMD + fracture) –  BMD -  vertebral fracture risk

10. Osteoporosis Drug Development 1942-2000 Estrogens vs. non-estrogens Clinical trials: small  large  very large BMD gave way to Fracture Placebo controlled Now have a number of drugs that reduce vertebral fracture risk over 3 years.

11. FDA’s Osteoporosis Guidance Document 1979 1984 1994

12. Osteoporosis Guidance 1979 Phase 3 studies – Randomized, double-blind, placebo-controlled and at least 24 months in duration Evaluating skeletal mass –Single photon absorptiometry –Total body neutron activation analysis

13. Osteoporosis Guidance 1979 Evaluating fractures –“Highly desirable” to measure fracture rate –However, will require large sample size Middle ground –Bone mass adequate surrogate if bone is normal –Fracture data required if bone is not normal

14. Osteoporosis Guidance 1984 vs. 1979 Prevention studies Dual photon absorptiometry Calcium and vitamin D supplementation

15. Osteoporosis Guidance 1994 vs. 1984 Estrogen vs. Non-Estrogen Preclinical data Skeletal assessment –DEXA Fracture assessment (vertebral) –Quantitative > Semi-quantitative

16. Osteoporosis Guidance 1994 vs. 1984 Approval for treatment of PMO based on 3- year clinical data, if: –bone quality normal in preclinical studies –positive trend (p<0.2) in 3-year fracture data –subset of patients have normal bone quality –BMD  by statistically and clinically significant degree –Fracture study must continue to 5 years or until definitive benefit shown

17. Current Regulatory Practice Estrogens –Prevention of PMO = BMD –Treatment of PMO = fracture SERMs and Non-Estrogens –Prevention of PMO = BMD + fracture –Treatment of PMO = fracture

18. The Future Guidance