FDA’s Osteoporosis Guidance

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

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

Abbreviations • Postmenopausal osteoporosis = PMO • Bone mineral density = BMD

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.”

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

Regulatory History of Non-Estrogens • Calcitonin • Fluoride • Bisphosphonates • SERM

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??

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

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

Osteoporosis Drug Development1942-2000 • 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.

FDA’s Osteoporosis Guidance Document • 1979 • 1984 • 1994

Osteoporosis Guidance1979 • 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

Osteoporosis Guidance1979 • 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

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

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

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

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

The Future Guidance

FDA’s Osteoporosis Guidance