# Presentation: 751417

## “Bridging What is Known and What is Not Known”FDA Perspective and Response

**Janet Woodcock, M.D.**
**Director, Center for Drug Evaluation and Research**
**Food and Drug Administration**

## Topics

- Role of FDA Drug Regulation
- Estrogen and progestin drugs approved for menopausal conditions
- Impact of WHI Results
- Question of generalizability of findings
- Implications of WHI for Risk Management
- Conclusions

## FDA Drug Regulation

- Applies to pharmaceuticals:  Demonstration of Safety and Effectiveness
- “Dietary Supplements” regulated under a different law - no FDA review of clinical data

## Requirements for Pharmaceuticals:  Effectiveness

- Demonstrated in “adequate and well controlled trials”
- Applies only to indications in label
- For chronic administration:  demonstration of long-term effectiveness not required
- Advertising limited to approved indications and must conform to the data

## Requirements for Pharmaceuticals:  Safety

- No drug is absolutely safe
- “Safety” = benefits exceed risks for defined population and use
- Longer term risks difficult to assess
- Challenges of randomized trials
- Positive benefit-risk may not apply to “off-label” use

## Estrogen and Progestin Drugs Approved for Menopausal Conditions

- Five approved combination products:  four oral, one transdermal patch
- Fifteen estrogen products:  oral, transdermal patches, injections, topical gel, vaginal ring
- Six progestins:  oral, injection and gel

## Approved Indications for Menopausal Conditions

- Vasomotor symptoms
- Vulvar vaginal atrophy
- Prevention of osteoporosis
- _Not_ approved for:
- Prevention of cardiovascular disease
- “Hormone replacement”

## Treatment of Vasomotor Symptoms:  Current Standards

- Trial design:  3 month placebo-controlled, multiple dose, 60-100 subjects/group
- Endpoints
- Clinically & statistically significant reduction in frequency and severity of hot flashes weeks 4-12.

## Treatment of Vulvar Vaginal Atrophy

- Trial design:	3 month placebo-					controlled, multiple dose,
- 				60-100 subjects/group
- Endpoints
- Statistically significant at 12 weeks:
- Symptom reduction
- Lowering of vaginal pH
- Improvement in maturation index

## Prevention of Osteoporosis

- Trial design:		2 yr placebo 						controlled, typically 					150-300 subjects
- Endpoints
- Lumbar spine bone mineral density

## Estrogens & Progestins, and Estrogens, Approved for Prevention of Postmenopausal Osteoporsis

- Product			Active Ingredients
- Activella			estradiol/norethindrone
- Femhrt			ethinyl estradiol/norethindrone
- Ortho-Prefest			estradiol/norgestimate
- Estrace			estradiol
- Ogen				estropipate
- Ortho-est			estropipate
- Vivelle (patch)		estradiol
- Climara (patch)		estradiol

## FDA- approved Non-estrogens for Treatment and Prevention of Premenopausal Osteoporosis

- 	Drug					Class
- Alendronate			Bisphosphonate
- Risedronate			Bisphosphonate
- Raloxifene			SERM

## “Pre-WHI”  Safety Labeling:  Prempro

- “Warnings” section:  known risks discussed
- Induction of malignant neoplasms, including reports of “moderately increased risk” of breast cancer
- Thromboembolic disorders including venous TE
- Precautions Section:  “A relationship between estrogen.. therapy and reduction of cardiovascular disease has not been proven”

## Impact of WHI Results on Menopausal Drug Development

- FDA considering public Advisory Committee Meeting
- Impact on current labels
- Trial length for safety data
- Trial size for population experience
- Generalizability of WHI results

## Generalizability of WHI Results:  What do results with Prempro imply for other estrogen/progestin drugs

- Two issues:
- 				Composition
- 				Dose

## Composition

- Prempro	.625 mg  conjugated equine 					estrogens (CEE)
- 		2.5 or 5.0 mg medroxyprogesterone acetate
- CEE	Complex mixture

## Composition of Premarin Component of Prempro

- Derived from pregnant mare’s urine
- “0.625 mg” is a convention:  does not quantitate amounts
- Multiple estrogen components:  pharmacologic characteristics of separate components not well characterized

## Sodium [Estrogen] Sulfate mg/.625 mg tablet

- Estrone					.370
- Equilin					.168
- 17-****- Dihydroequilin			.102
- 17-****- Estradiol				.027
- 17-****- Dihydroequilin			.011
- 17-****- Dihydroequilenin			.011
- 17-****- Dihydroequilenin			.015
- 17-****- Estradiol				.005

-   8,9-Dehydroestrone			.026
-   Equilenin					.015

## Composition: Estrogens

- Premarin contains unique equine estrogens in addition to estrone/estradiol
- Equine estrogens may have different pharmacodynamic properties
- Only two other approved products contain equine estrogens

## Composition:  Progestins

- Premarin also contains progestins - activity not known
- Medroxyprogesterone acetate not a component of any other combination product

## Dosage

- Original estrogenic potency assignment based on a rat bioassay
- Effects on rat do not parallel human
- Pharmacokinetic difference among estrogens

## Pharmacokinetic Studies

- <date/time>

- _Estrogen_     	     _Estrone_        _Equilin_        _8,9-DHE_
- Measured dose
- or AUC
- _mg per 1.25mg dose__	__	_.740		.336		.052
- ng. Hr/ml AUC
- Total plasma			94.2		43.1		13.6
- 	Ketone
- Unconj. plasma	 		4.08	             1.2		.07
-   Ketone
- Total plasma		        	8.57		10.6		6.62
-    17 **** diol
- Unconj. Plasma		        	0.66		1.06		0.33
-    17 **** diol

## Synthetic Generic Conjugated Estrogens

Website:
  http://www.fda.gov/cder/cepage.htm

- Website:
-   http://www.fda.gov/cder/cepage.htm

## Generalizability:  Dose

- Drug toxicities are frequently dose related
- WHI toxicity findings are generally congruent with potential “class” effects of estrogen and progestin
- Not possible to extrapolate dose/toxicity findings directly to other related products

## Risk Management Implications of WHI findings

- Prevention indications:  Need to be assured of positive benefit/risk analysis in people without symptoms
- Minimizing risk:  Data questions
- Relationship of dose or duration to toxicity
- Relationship of route of administration to toxicity

## Risk Management Implications of WHI findings

- Maximizing benefit
- Women with more severe menopausal symptoms
- Women at higher risk of osteoporosis

## Risk Management:  Information Dissemination

- Informative product labels
- Patient education efforts by companies
- Responsible advertising & promotion

## Summary

- WHI results provide important additional risk information on estrogen/progestin combinations
- Quantitative extrapolation to similar products not possible
- There are implications for new drug development in this area
- It is imperative that accurate information be available to prescribers and patients