FDA’s Osteoporosis GuidanceFDA’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