1. Food and Drug Administration Regulatory Implications of The WHI Study Eric Colman, MD Center for Drug Evaluation and Research Division of Metabolic and Endocrine Drugs October 7, 2003

2. Food and Drug Administration Outline  Terminology  Regulatory history of estrogens and estrogen + progestin formulations  Estrogen + progestin formulations FDA approved for the prevention of osteoporosis  Labeling changes made in response to WHI

3. Food and Drug Administration Terminology  Estrogen (E) plus progestin (P) = E + P  Conjugated equine estrogens = CEE  Medroxyprogesterone acetate = MPA  CEE/MPA = Prempro/Premphase  Postmenopausal osteoporosis = PMO  Bone mineral density = BMD  Randomized controlled trial = RCT

4. Food and Drug Administration Regulatory History of E and E + P  1942 - CEE approved for menopausal symptoms  1972 - estrogens “probably effective” for select cases of osteoporosis (DESI)  1986 - estrogens “effective” therapy for osteoporosis  1990s - “management” and “prevention”  Bone mass, not fracture, basis for osteoporosis indication

5. Food and Drug Administration Regulatory History con’t  1994 - CEE/MPA approved for the prevention of osteoporosis  Wyeth Ayerst agrees to post-approval study of lower doses of CEE/MPA  1994 - Agency updated Osteoporosis Guidance  Epi studies support fracture efficacy  Prevention of PMO indication requires 2 year BMD study

6. Food and Drug Administration Approval of E and E + P for the Prevention of PMO  Designated a DESI drug………………OR  Placebo RCT  2 years in duration  Primary endpoint - lumbar spine BMD  Women with normal or osteopenic BMD  Sample size generally less than 500

7. Food and Drug Administration Approval of Non-Estrogens  Treatment Indication:  3-year RCT demonstrating fracture efficacy  Prevention Indication :  2-year RCT demonstrating BMD efficacy  Favorable preclinical profile  Large clinical databases  ~5,000 to 15,000 trial participants

8. Food and Drug Administration Regulatory Status of E + P  E + P approved for the prevention of PMO  No E + P approved for the treatment of PMO  Treatment = fracture reduction in subjects with osteoporosis at baseline  Prevention = preserves or increases BMD in subjects without osteoporosis at baseline

9. Food and Drug Administration E + P and E Approved for the Prevention of PMO Product Active Ingredients Doses (mg) Prempro CEE/MPA0.625/5.0 0.625/2.5 0.45/1.5 0.30/1.5 Premarin CEE0.625 0.45 0.30

10. Food and Drug Administration E + P and E Approved for the Prevention of PMO Product Active Ingredients Doses (mg) Activella estradiol/norethindrone 1.0/0.5 Femhrt ethinyl estradiol/norethindrone 0.5/1.0 Ortho-Prefest estradiol/norgestimate 1.0/0.09 Estrace estradiol 0.5/1.0/2.0 Ogen estropipate 0.75 Ortho-Est estropipate 0.75 Vivelle (patch) estradiol 0.025-0.1 Climara (patch) estradiol 0.025-0.1

11. Food and Drug Administration Summary  Several E + P products in addition to Prempro are approved for the prevention of PMO  No E + P product is approved for the treatment of PMO  WHI provides strong evidence that E + P reduces the risk for osteoporotic fracture  “……no net benefit, even in women considered to be at high risk of fracture.”

12. Food and Drug Administration Labeling Changes  Black box warning  Clinical Studies  Indications and Usage  Warnings  Precautions  Dosage and Administration

13. Food and Drug Administration Black Box WARNING Estrogens and progestins should not be used for the prevention of cardiovascular disease. The Women’s Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women during 5 years of treatment with conjugated equine estrogens (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg) relative to placebo (see CLINICAL PHARMACOLOGY, Clinical Studies)…...

14. Food and Drug Administration Black Box con’t …Other doses of conjugated estrogens and medroxyprogesterone acetate, and other combinations of estrogens and progestins were not studied in the WHI and, in the absence of comparable data, these risks should be assumed to be similar. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

15. Food and Drug Administration Indications and Usage PREMPRO or PREMPHASE therapy is indicated in women who have a uterus for the following: 1. Treatment of moderate to severe vasomotor symptoms associated with the menopause. 2. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.

16. Food and Drug Administration Indications and Usage con’t 3. Prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medications should be carefully considered.

17. Food and Drug Administration Dosage and Administration Use of estrogens, alone or in combination with a progestin, should be limited to the shortest duration consistent with treatment goals and risks for the individual women. Patients should be re-evaluated periodically as clinically necessary (see BOXED WARNING and WARNINGS)……

18. Food and Drug Administration Dosage and Administration con’t Prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non- estrogen medications should be carefully considered…………………. Patients should be treated with the lowest effective dose. Generally women should be started at 0.3 mg/1.5 mg PREMPRO daily. Dosage may be adjusted depending on individual clinical and bone mineral density responses. This dose should be periodically reassessed by the healthcare provider……………………….

19. Food and Drug Administration Issues for the Committee 1. Comment on the revisions made thus far to the Prempro labeling

20. Food and Drug Administration Issues for the Committee 2. Discuss the implications of the WHI trial results for the future development, testing, and potential approval of E + P drug products for the prevention and/or treatment of postmenopausal osteoporosis.

21. Food and Drug Administration Issues for the Committee 3. Provide other comments or recommendations related to the WHI trial, or to regulation of E + P products for the prevention and/or treatment of postmenopausal osteoporosis