FDA

1
FDAs Osteoporosis Guidance

• Center for Drug Evaluation and Research
• Division of Metabolic and Endocrine Drugs
• Eric Colman, MD
• September 25, 2002

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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

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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.

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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

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Regulatory History of Non-Estrogens

• Calcitonin
• Fluoride
• Bisphosphonates
• SERM

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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??

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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

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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

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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.

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FDAs Osteoporosis Guidance Document

• 1979
• 1984
• 1994

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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

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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

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Osteoporosis Guidance 1984 vs. 1979

• Prevention studies
• Dual photon absorptiometry
• Calcium and vitamin D supplementation

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Osteoporosis Guidance 1994 vs. 1984

• Estrogen vs. Non-Estrogen
• Preclinical data
• Skeletal assessment
• DEXA
• Fracture assessment (vertebral)
• Quantitative gt Semi-quantitative

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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 (plt0.2) 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

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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

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The Future Guidance