# Presentation: 915559

## Regulatory Implications of The WHI Study

- Eric Colman, MD
- Center for Drug Evaluation and Research
- Division of Metabolic and Endocrine Drugs
- October 7, 2003

## 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

## 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

## 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

## 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

## 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

## 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

## 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

## E + P and E Approved for the Prevention of PMO

**Product**	            **Active Ingredients**	           **Doses (mg)**
- Prempro		   CEE/MPA			0.625/5.0
- 							0.625/2.5
- 							0.45/1.5
- 							0.30/1.5
- Premarin		     CEE				0.625
- 							0.45
- 							0.30

##  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

## 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.”

## Labeling Changes 

**Black box warning**
- Clinical Studies
**Indications and Usage**
- Warnings
- Precautions
**Dosage and 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)......

## 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.

## 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.

## 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.

## 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)......

## 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............................

## Issues for the Committee

- 1.  Comment on the revisions made thus far to the Prempro labeling

## 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.

## 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