Guidance for Industry
Estrogen and Estrogen/Progestin Drug
Products to Treat Vasomotor Symptoms
and Vulvar and Vaginal Atrophy
Symptoms  Recommendations for
Clinical Evaluation
DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.
Comments and suggestions regarding this draft document should be submitted within 60 days of
publication in the Federal Register of the notice announcing the availability of the draft
guidance.  Submit comments to Dockets Management Branch (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD  20852.  All comments should be
identified with the docket number listed in the notice of availability that publishes in the Federal
Register.
For questions on the content of the draft document contact Margaret Kober at 301-827-4243
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
January 2003
Clinical/Medical 
G:\5412dft.doc
01/02/03 Guidance for Industry
Estrogen and Estrogen/Progestin Drug
Products to Treat Vasomotor Symptoms
and Vulvar and Vaginal Atrophy
Symptoms  Recommendations for
Clinical Evaluation
Additional copies are available from:
The Division of Drug Information (HFD-240)
Center for Drug Evaluation and Research 
5600 Fishers Lane
Rockville, MD  20857
(Tel) 301-827-4573
Internet at http://www.fda.gov/cder/guidance/index.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
January 2003  
Clinical/Medical
G:\5412dft.doc
01/02/03 Draft  Not for Implementation
Table of Contents
I. INTRODUCTION.................................................................................................................1
II. BACKGROUND...................................................................................................................1
III. DRUG PRODUCTS CONTAINING ESTROGEN ALONE............................................2
A. Indications.........................................................................................................................................2
1. Moderate to severe vasomotor symptoms associated with the menopause......................................2
2. Moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause.......2
B. Study Considerations.......................................................................................................................2
C. Inclusion and Exclusion Criteria....................................................................................................3
D. Monitoring........................................................................................................................................4
E.  Primary Endpoints.........................................................................................................................4
F. Study Analysis..................................................................................................................................4
IV. DRUG PRODUCTS CONTAINING ESTROGEN PLUS PROGESTIN.......................5
A. Indications.........................................................................................................................................5
1. Estrogen Component........................................................................................................................5
2. Progestin Component......................................................................................................................5
B. Study Considerations.......................................................................................................................5
C. Inclusion and Exclusion Criteria....................................................................................................6
D. Monitoring........................................................................................................................................6
E. Primary Endpoints...........................................................................................................................8
APPENDIX:  HISTOLOGIC DESCRIPTIONS RECOMMENDED FOR USE WHEN
READING ENDOMETRIAL BIOPSY SLIDES.......................................................................9
G:\5412dft.doc
01/02/03 Draft  Not for Implementation
1
Guidance for Industry
1
2
Estrogen and Estrogen/Progestin Drug Products to Treat Vasomotor
3
Symptoms and Vulvar and Vaginal Atrophy Symptoms 
4
Recommendations for Clinical Evaluation
5
6
7
8
9 This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's)
10 current thinking on this topic.  It does not create or confer any rights for or on any person and
11 does not operate to bind FDA or the public.  An alternative approach may be used if such
12 approach satisfies the requirements of the applicable statutes and regulations.
13
14
15
16 I. INTRODUCTION
17
18 This guidance updates the final guidance Guidance for Clinical Evaluation of Combination
19 Estrogen/Progestin - Containing Drug Products Used for Hormone Replacement Therapy of
20 Postmenopausal Women, published in March 1995.  The guidance is intended to provide
21 recommendations to industry for studies of estrogen and estrogen/progestin drug products for the
22 treatment of moderate to severe vasomotor symptoms associated with the menopause and
23 moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause.  The
24 guidance also addresses the reduction of the risk of endometrial hyperplasia or adenocarcinoma
25 from estrogen exposure in postmenopausal women who have a uterus. For other indications,
26 such as prevention of osteoporosis, sponsors are asked to direct inquiries to the appropriate
27 CDER Office of New Drugs review division.2
28
29
30 II. BACKGROUND
31
32 Estrogen therapy has been used for over one-half century for the management of menopausal
33 symptoms, including vulvar and vaginal atrophy and vasomotor symptoms.  Since the early
34 1980s, estrogen has also been used to help prevent the loss of bone mineral density. 
35
36 The use of estrogen alone (unopposed by progestin drugs) therapy in women who have a uterus
37 is associated with an increased incidence of endometrial hyperplasia and adenocarcinoma of the
38 endometrium.  A regimen that combines a progestin drug with estrogen has been shown to
                                                          
1 This guidance was developed by the Division of Reproductive and Urologic Drug Products (DRUDP) in the Center
for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA).
2 Drugs for the prevention or treatment of osteoporosis are reviewed by the Division of Metabolic and Endocrine
Drug Products, Office of New Drugs, CDER. 
G:\5412dft.doc
1 Draft  Not for Implementation
39 reduce the risk of estrogen-induced endometrial hyperplasia without compromising the positive
40 effects of estrogen on vasomotor symptoms, vulvar and vaginal atrophy symptoms, or bone
41 mineral density.
42
43 Although adding progestins to estrogens decreases the risk of endometrial hyperplasia in
44 postmenopausal women, the addition of progestins to estrogen therapy may be associated with
45 increases in the risk of a variety of serious adverse events, such as breast cancer,
46 thromboembolic events, and myocardial infarction.  Therefore, this guidance encourages
47 sponsors to develop the lowest doses and exposures for both estrogens and progestins for
48 indications sought, even though specific relationships between dose, exposure, and risk of
49 adverse events may not be known.  Sponsors are encouraged to investigate dosing schedules and
50 drug delivery systems that can achieve efficacy with lowest possible exposures.
51
52
53 III. DRUG PRODUCTS CONTAINING ESTROGEN ALONE
54
55 A. Indications
56
57 There are two symptomatic indications for estrogen alone therapy. 
58
59 1. Moderate to severe vasomotor symptoms associated with the menopause
60
61 Vasomotor symptoms in postmenopausal women are commonly known as hot flushes or
62 hot flashes.  The severity of vasomotor symptoms are defined clinically as follows:
63
64 Mild: sensation of heat without sweating
65 Moderate: sensation of heat with sweating, able to continue activity
66 Severe: sensation of heat with sweating, causing cessation of activity
67
68 2. Moderate to severe symptoms of vulvar and vaginal atrophy associated with the
69 menopause  
70
71 Patient self-assessed symptoms of vulvar and vaginal atrophy include:
72
73   Vaginal dryness (none, mild, moderate or severe)
74   Vaginal and/or vulvar irritation/itching (none, mild, moderate or severe)
75   Dysuria (none, mild, moderate or severe)
76   Vaginal pain associated with sexual activity (none, mild, moderate or severe)
77   Vaginal bleeding associated with sexual activity (presence vs. absence)
78
79 B. Study Considerations
80
81 The Agency recommends that prior to initiating phase 3 development, adequate dose ranging
82 studies be conducted to identify the doses to be studied in the proof of efficacy studies.  We
83 recommend conducting one or more placebo-controlled trials to support efficacy of each
84 indication in Section III.A.  One adequately designed clinical trial to study both indications
85 concurrently is possible.  We recommend that studies be randomized, double-blinded and of 12-
G:\5412dft.doc
2 Draft  Not for Implementation
86 week duration.  In addition, we recommend that studies identify the lowest effective dose by
87 including an ineffective dose as one of the doses evaluated.
88
89 If the drug product is considered to be a new molecular entity or poses an unexpected safety
90 concern, two placebo-controlled phase 3 clinical trials are recommended to establish safety and
91 efficacy. 
92
93 C. Inclusion and Exclusion Criteria
94
95 We recommend that:
96
97  Only postmenopausal women be included in studies.  We define postmenopausal as 12
98 months of spontaneous amenorrhea or 6 months of spontaneous amenorrhea with serum
99 FSH levels > 40 mIU/ml or 6 weeks postsurgical bilateral oophorectomy with or without
100 hysterectomy.
101  For the indication of treatment of moderate to severe vasomotor symptoms, study
102 participants be enrolled who have a minimum of 7 to 8 moderate to severe hot flushes per
103 day, or 50 to 60 per week at baseline.
104  For the indication of treatment of moderate to severe symptoms of vulvar and vaginal
105 atrophy, study participants be enrolled who have self-identified at least one moderate to
106 severe symptom (see Section III.A.2) that is the most bothersome to her, have no greater
107 than 5 percent superficial cells on a vaginal smear, and have a vaginal pH > 5.0.
108   Study participants not be taking estrogen alone or estrogen/progestin containing drug
109 products.  The following washout periods are recommended before baseline assessments
110 are made for subjects previously on estrogen alone or estrogen/progestin containing
111 products: 
112  1 week or longer for prior vaginal hormonal products (rings, creams, gels)
113  4 weeks or longer for prior transdermal estrogen alone or estrogen/progestin products
114  8 weeks or longer for prior oral estrogen and/or progestin therapy
115  8 weeks or longer for prior intrauterine progestin therapy  
116  3 months or longer for prior progestin implants and estrogen alone injectable drug
117 therapy
118  6 months or longer for prior estrogen pellet therapy or progestin injectable drug
119 therapy
120  Women >40 years have documentation of a negative screening mammogram (obtained at
121 screening or within 9 months of study enrollment) and normal clinical breast examination
122 prior to enrollment in clinical studies.  Findings indicating any suspicion of breast
123 malignancy would result in exclusion from enrollment. 
124  All subjects who have a uterus have endometrial biopsy performed at screening.
125 Findings indicating endometrial hyperplasia or cancer would result in exclusion from
126 enrollment. 
G:\5412dft.doc
3 Draft  Not for Implementation
127
128 D. Monitoring
129
130 We recommend that:
131
132   All subjects who have a uterus undergo an endometrial biopsy at end-of-study.
133   Any new findings noted during the conduct of the study or during the end-of-study
134 physical examination (including findings related to the breast) receive careful and
135 appropriate evaluation and be monitored until there is complete clinical resolution of any
136 diagnosed condition.
137   Sponsors provide plans for monitoring and/or reducing the risk of adverse endometrial
138 effects in women who have a uterus.
139   Safety assessments of lipids and of carbohydrate and coagulation parameters
140 (antithrombin III, factor V Leiden, protein-C and protein-S) be conducted.
141   Serum levels of the parent compounds and metabolites be measured.
142 E.  Primary Endpoints
143
144 For the treatment of moderate to severe vasomotor symptoms, we recommend the following co-
145 primary endpoints:
146
147   Mean change in frequency of moderate to severe vasomotor symptoms from baseline to
148 week 4 
149   Mean change in frequency of moderate to severe vasomotor symptoms from baseline to
150 week 12
151   Mean change in severity of moderate to severe vasomotor symptoms from baseline to
152 week 4
153   Mean change in severity of moderate to severe vasomotor symptoms from baseline to
154 week 12
155
156 For the treatment of moderate to severe symptoms of vulvar and vaginal atrophy, we recommend
157 the following co-primary endpoints.
158
159   Mean change from baseline to week 12 in the moderate to severe symptom that has been
160 identified by the patient as being the most bothersome to her
161   Mean change from baseline to week 12 in vaginal pH
162   Mean change from baseline to week 12 in vaginal maturation index (parabasal and
163 superficial cells)
164 F. Study Analysis
165
166 For estrogen alone products intended to treat moderate to severe vasomotor symptoms, we
167 recommend that the primary efficacy analyses show a clinically and a statistically significant
G:\5412dft.doc
4 Draft  Not for Implementation
168 reduction, within 4 weeks of initiation of treatment and maintained throughout 12 weeks of
169 treatment, in both the frequency and severity of hot flushes in the treated groups compared with
170 the control groups.  Subjective measures (e.g., daily patient diary entries) can be used as primary
171 efficacy endpoints.  Alternatively, objective measures (e.g., thermography) can be used both as
172 primary efficacy endpoints and as validation of subjective endpoints.  We recommend that study
173 results clearly identify the lowest effective dose of estrogen to support the indication by
174 demonstrating an ineffective lower dose.
175
176 For estrogen alone drug products intended to treat moderate to severe symptoms of vulvar and
177 vaginal atrophy, we recommend that the primary efficacy analyses demonstrate a statistically
178 significant improvement versus placebo from baseline to week 12 of treatment in all three of the
179 following parameters:
180
181 1.  Maturation Index (decrease of parabasal vaginal cells and increase in superficial
182 vaginal cells) 
183 2.  Lowering of the vaginal pH
184 3.  The moderate to severe symptom identified by the subject as being most bothersome
185 to her
186
187
188 IV. DRUG PRODUCTS CONTAINING ESTROGEN PLUS PROGESTIN 
189
190 The approval of specific fixed dose estrogen/progestin drug products for estrogen class labeling
191 indications in women who have a uterus will be based on two criteria: (1) that each component
192 contribute to the efficacy and safety as defined in the combination drug policy (see 21 CFR
193 300.50) and (2) the determination that a combination drug contains the lowest effective dose of
194 each of its active components for their respective labeled indications.
195
196 A. Indications
197
198 1. Estrogen Component
199
200 The symptomatic indications for estrogen/progestin therapy are the same as those previously
201 discussed under Section III.A of this guidance. 
202
203 2. Progestin Component
204
205 The progestin component is added to estrogen alone regimens for safety purposes to oppose the
206 adverse effects of estrogen on the endometrium in women who have a uterus.  We recommend
207 that sponsors propose low-dose combination estrogen/progestin regimens and dosing schedules
208 that demonstrate endometrial safety and have acceptable endometrial bleeding profiles.
209
210 B. Study Considerations
211
212 To support the indication of the treatment of moderate to severe vasomotor symptoms or the
213 treatment of moderate to severe symptoms of vulvar and vaginal atrophy, see Section III.B in
214 this guidance.
G:\5412dft.doc
5 Draft  Not for Implementation
215
216 To demonstrate protection of the endometrium, we recommend that a single, 12-month,
217 randomized, double-blind, dose-ranging phase 3 clinical trial be conducted and include two or
218 more progestin drug treatment arms for each estrogen dose studied.  However, the indications in
219 Section III.A can be studied as part of the 12-month endometrial protection study, provided all
220 entrance criteria for each indication are met and the study is powered adequately for each
221 endpoint.  We recommend that study results clearly identify the lowest effective dose of estrogen
222 (as described in Section III.B) and the lowest effective dose of progestin to support endometrial
223 safety by demonstrating an ineffective lower dose on the endometrium. 
224
225 If the drug to be studied is considered to be a new molecular entity or if it poses unique safety
226 concerns, two placebo-controlled phase 3 clinical trials are recommended to establish safety and
227 efficacy. 
228
229 C. Inclusion and Exclusion Criteria
230
231 Please refer to the criteria set out in Section III.C., except as specified below.
232
233 We recommend that:
234
235  All subjects have a uterus and have an evaluable screening endometrial biopsy (i.e.,
236 endometrial tissue sufficient for diagnosis).  Findings indicating endometrial hyperplasia
237 or cancer would result in exclusion from enrollment and subjects would be referred for
238 standard of care clinical management.
239  A negative screening mammogram (obtained at screening or within 3 months of study
240 enrollment) and normal clinical breast examination be documented prior to enrollment in
241 clinical studies for women > 40 years old. Findings indicating any suspicion of breast
242 malignancy would result in exclusion from enrollment. 
243
244 D. Monitoring
245
246 We recommend that:
247
248  The endometrial tissue obtained by endometrial biopsy at screening, during the conduct
249 of the study, and at the end-of-study be processed in the same manner by a central
250 laboratory.  
251  Endometrial biopsies and not uterine ultrasounds be used for the evaluation of
252 endometrial hyperplasia (sponsors interested in establishing a correlation between
253 transvaginal ultrasound and endometrial biopsy results may perform transvaginal
254 ultrasound immediately preceding endometrial biopsies).  
255  A single pathologist reader (any one of the three blinded pathologists) initially assess the
256 slides from the endometrial biopsies obtained at screening or because of participant
257 bleeding while on study drug (safety reading).  
G:\5412dft.doc
6 Draft  Not for Implementation
258  For the efficacy evaluation, three independent expert pathologists, blinded to treatment
259 group and to each others readings, determine the diagnosis for endometrial biopsy slides
260 during the conduct of the study.
261  Curricula vitae for participating pathologists be provided to the FDA and document
262 expertise in gynecologic pathology.
263  Participating study pathologists be from different institutions with independent fiduciary
264 and organizational reporting, and these pathologists not meet to review slides before or
265 during the conduct of the clinical trial.  
266  Standardized criteria as provided in Blausteins pathology text (Pathology of the Female
267 Genital Tract) be used for the diagnosis of endometrial hyperplasia (see Appendix for
268 recommended histologic characteristics of the endometrium). 
269  Endometrial polyps be fully characterized as to the glandular proliferation and atypia (see
270 Appendix for additional histologic characteristics of the specimen). 
271  Subjects found to have endometrial hyperplasia or adenocarcinoma of the endometrium
272 be excluded from further drug treatment (if discovered during study drug treatment
273 period) and referred for standard of care clinical management and followed to complete
274 resolution, and the report of any medical or surgical procedures and the resultant
275 pathology be provided to the FDA.  
276  If hyperplasia is diagnosed by the single safety reader for a subject who has bled while on
277 study drug, this diagnosis be maintained for the efficacy evaluation and the slides become
278 part of the slide set given to the two other pathologists for reading.  
279  For the efficacy evaluation, the concurrence of two of the three pathologists be accepted
280 as the final diagnosis.  If there is no agreement among the three pathologists, the most
281 severe pathologic diagnosis (i.e., atypical hyperplasia > complex hyperplasia > simple
282 hyperplasia > benign endometrium) would be used as the final diagnosis.  
283  The slide set distributed to each of the three pathologists for the end-of-study pathology
284 review incorporate control sides representing a randomly selected 10 percent of the
285 screening normal slides and all slides from subjects excluded for the diagnosis of
286 hyperplasia or cancer to insure quality control. 
287  Digital recording of diagnostic areas of the slides be maintained by the central laboratory
288 and be made available upon FDA request. 
289  Any new findings noted during the conduct of the study and on end-of-study physical
290 examination (including findings related to the breast) receive careful and appropriate
291 evaluation and be monitored until there is complete clinical resolution of any diagnosed
292 condition.  
293  Safety assessments of lipids and of carbohydrate and coagulation parameters
294 (antithrombin III, factor V Leiden, protein-C and protein-S) be conducted. 
295  Serum levels of the parent compounds and metabolites be measured.
296
G:\5412dft.doc
7 Draft  Not for Implementation
297 E.  Primary Endpoints
298
299 For protection of the endometrium, we recommend the evaluation of the incidence rate of
300 endometrial hyperplasia at 12 months.
301
302 F.  Study Analysis
303
304 See Section III.F. for analysis of primary endpoints for treatment of moderate or severe
305 vasomotor symptoms or moderate to severe symptoms of vulvar and vaginal atrophy associated
306 with the menopause.  The objective of the clinical trial is to demonstrate the lowest effective
307 dose of the progestin drug that reduces the estimated risk of endometrial hyperplasia after 1 year
308 of estrogen/progestin treatment.  The reported 1-year background incidence rate for endometrial
309 hyperplasia in postmenopausal women and in postmenopausal women treated with currently
310 marketed combination estrogen/progestin drugs is approximately 0-1 percent.  We recommend
311 that the results from the clinical trial demonstrate a hyperplasia rate that is  1 percent with an
312 upper bound of the one-sided 95 percent confidence interval for that rate that does not exceed 4
313 percent.  The frequency of atypical hyperplasia and cancer are important additional factors to be
314 considered in determining approvability of the drug product.  The incidence of hyperplastic
315 polyps and associated atypia would be considered in the safety review.
316
G:\5412dft.doc
8 Draft  Not for Implementation
317 APPENDIX:  HISTOLOGIC DESCRIPTIONS RECOMMENDED FOR USE
318 WHEN READING ENDOMETRIAL BIOPSY SLIDES  
319
320
321
322 Histologic Characteristics of the Endometrium 
323
324 0.   No tissue
325
326 1.   Tissue insufficient for diagnosis
327
328 2.   Atrophic
329
330 3.   Inactive
331
332 4.   Proliferative
333
334 a. Weakly proliferative
335
336 b. Active proliferative
337
338 c. Disordered proliferative
339
340 5.   Secretory
341
342 a. Cyclic type
343
344 b. Progestational type (including stromal decidualization)
345
346 6.   Menstrual type
347
348 7.   Simple hyperplasia without atypia
349
350 8.   Simple hyperplasia with atypia
351
352 9.   Complex hyperplasia without atypia
353
354 10. Complex hyperplasia with atypia  
355
356 11. Carcinoma (specify type)
357
G:\5412dft.doc
9 Draft  Not for Implementation
358
359 Additional Histologic Characteristics
360
361 If there are any polyps, please specify the type or types. 
362
363 Functional
364 Atrophic
365 Hyperplastic without atypia
366 Hyperplastic with atypia
367 Carcinomatous
368
369 If there is any stromal tissue, please specify the type or types.
370
371 Smooth muscle tissue, normal
372 Features suggestive of adenomyoma
373 Features suggestive of stromal nodule
374 Sarcoma (specify type)
375
376 If there is any metaplasia, please specify the type or types.
377
378 Squamous
379 Papillary
380 Eosinophilic
381 Ciliated
382 Mucinous
383 Syncytial
384 Other type (specify type)
385
386 If there is any cervical tissue, please specify the type or types.
387
388 Fragments of negative cervical epithelium 
389 Endocervical polyp
390 Atypical endocervical glandular epithelium
391 Atypical squamous metaplasia
392 Squamous dysplasia
393 Cervical carcinoma 
394
395
G:\5412dft.doc
10