Estrogen and Estrogen/Progestin Drug Products to Treat Vasomotor Symptoms and Vulvar and Vaginal Atrophy Symptoms — Recommendations for Clinical Evaluation

Administrative draft guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

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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
DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft
guidance.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

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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

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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

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Guidance for Industry1
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
This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's)	9
current thinking on this topic. It does not create or confer any rights for or on any person and	10
does not operate to bind FDA or the public. An alternative approach may be used if such	11
approach satisfies the requirements of the applicable statutes and regulations.	12
13
14
15
I. 	INTRODUCTION	16
17
This guidance updates the final guidance Guidance for Clinical Evaluation of Combination	18
Estrogen/Progestin - Containing Drug Products Used for Hormone Replacement Therapy of	19
Postmenopausal Women, published in March 1995. The guidance is intended to provide	20
recommendations to industry for studies of estrogen and estrogen/progestin drug products for the	21
treatment of moderate to severe vasomotor symptoms associated with the menopause and	22
moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. The	23
guidance also addresses the reduction of the risk of endometrial hyperplasia or adenocarcinoma	24
from estrogen exposure in postmenopausal women who have a uterus. For other indications,	25
such as prevention of osteoporosis, sponsors are asked to direct inquiries to the appropriate	26
CDER Office of New Drugs review division.2
27
28
29
II. 	BACKGROUND	30
31
Estrogen therapy has been used for over one-half century for the management of menopausal	32
symptoms, including vulvar and vaginal atrophy and vasomotor symptoms. Since the early	33
1980s, estrogen has also been used to help prevent the loss of bone mineral density.	34
35
The use of estrogen alone (unopposed by progestin drugs) therapy in women who have a uterus	36
is associated with an increased incidence of endometrial hyperplasia and adenocarcinoma of the	37
endometrium. A regimen that combines a progestin drug with estrogen has been shown to	38
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.

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reduce the risk of estrogen-induced endometrial hyperplasia without compromising the positive	39
effects of estrogen on vasomotor symptoms, vulvar and vaginal atrophy symptoms, or bone	40
mineral density.	41
42
Although adding progestins to estrogens decreases the risk of endometrial hyperplasia in	43
postmenopausal women, the addition of progestins to estrogen therapy may be associated with	44
increases in the risk of a variety of serious adverse events, such as breast cancer,	45
thromboembolic events, and myocardial infarction. Therefore, this guidance encourages	46
sponsors to develop the lowest doses and exposures for both estrogens and progestins for	47
indications sought, even though specific relationships between dose, exposure, and risk of	48
adverse events may not be known. Sponsors are encouraged to investigate dosing schedules and	49
drug delivery systems that can achieve efficacy with lowest possible exposures.	50
51
52
III. 	DRUG PRODUCTS CONTAINING ESTROGEN ALONE	53
54
A. 	Indications	55
56
There are two symptomatic indications for estrogen alone therapy.	57
58
1. 	Moderate to severe vasomotor symptoms associated with the menopause	59
60
Vasomotor symptoms in postmenopausal women are commonly known as hot flushes or	61
hot flashes. The severity of vasomotor symptoms are defined clinically as follows:	62
63
Mild: 	sensation of heat without sweating	64
Moderate: 	sensation of heat with sweating, able to continue activity	65
Severe: 	sensation of heat with sweating, causing cessation of activity	66
67
2. 	Moderate to severe symptoms of vulvar and vaginal atrophy associated with the	68
menopause	69
70
Patient self-assessed symptoms of vulvar and vaginal atrophy include:	71
72
• 	Vaginal dryness (none, mild, moderate or severe)	73
• 	Vaginal and/or vulvar irritation/itching (none, mild, moderate or severe)	74
• 	Dysuria (none, mild, moderate or severe)	75
• 	Vaginal pain associated with sexual activity (none, mild, moderate or severe)	76
• 	Vaginal bleeding associated with sexual activity (presence vs. absence)	77
78
B. 	Study Considerations	79
80
The Agency recommends that prior to initiating phase 3 development, adequate dose ranging	81
studies be conducted to identify the doses to be studied in the proof of efficacy studies. We	82
recommend conducting one or more placebo-controlled trials to support efficacy of each	83
indication in Section III.A. One adequately designed clinical trial to study both indications	84
concurrently is possible. We recommend that studies be randomized, double-blinded and of 12-	85

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week duration. In addition, we recommend that studies identify the lowest effective dose by	86
including an ineffective dose as one of the doses evaluated.	87
88
If the drug product is considered to be a new molecular entity or poses an unexpected safety	89
concern, two placebo-controlled phase 3 clinical trials are recommended to establish safety and	90
efficacy.	91
92
C. 	Inclusion and Exclusion Criteria	93
94
We recommend that:	95
96
• 	Only postmenopausal women be included in studies. We define postmenopausal as 12	97
months of spontaneous amenorrhea or 6 months of spontaneous amenorrhea with serum	98
FSH levels > 40 mIU/ml or 6 weeks postsurgical bilateral oophorectomy with or without	99
hysterectomy.	100
• 	For the indication of treatment of moderate to severe vasomotor symptoms, study	101
participants be enrolled who have a minimum of 7 to 8 moderate to severe hot flushes per	102
day, or 50 to 60 per week at baseline.	103
• 	For the indication of treatment of moderate to severe symptoms of vulvar and vaginal	104
atrophy, study participants be enrolled who have self-identified at least one moderate to	105
severe symptom (see Section III.A.2) that is the most bothersome to her, have no greater	106
than 5 percent superficial cells on a vaginal smear, and have a vaginal pH > 5.0.	107
• 	Study participants not be taking estrogen alone or estrogen/progestin containing drug	108
products. The following washout periods are recommended before baseline assessments	109
are made for subjects previously on estrogen alone or estrogen/progestin containing	110
products:	111
— 1 week or longer for prior vaginal hormonal products (rings, creams, gels)	112
— 4 weeks or longer for prior transdermal estrogen alone or estrogen/progestin products	113
— 8 weeks or longer for prior oral estrogen and/or progestin therapy	114
— 8 weeks or longer for prior intrauterine progestin therapy	115
— 3 months or longer for prior progestin implants and estrogen alone injectable drug	116
therapy	117
— 6 months or longer for prior estrogen pellet therapy or progestin injectable drug	118
therapy	119
• 	Women >40 years have documentation of a negative screening mammogram (obtained at	120
screening or within 9 months of study enrollment) and normal clinical breast examination	121
prior to enrollment in clinical studies. Findings indicating any suspicion of breast	122
malignancy would result in exclusion from enrollment.	123
• 	All subjects who have a uterus have endometrial biopsy performed at screening.	124
Findings indicating endometrial hyperplasia or cancer would result in exclusion from	125
enrollment.	126

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127
D. 	Monitoring	128
129
We recommend that:	130
131
• 	All subjects who have a uterus undergo an endometrial biopsy at end-of-study.	132
• 	Any new findings noted during the conduct of the study or during the end-of-study	133
physical examination (including findings related to the breast) receive careful and	134
appropriate evaluation and be monitored until there is complete clinical resolution of any	135
diagnosed condition.	136
• 	Sponsors provide plans for monitoring and/or reducing the risk of adverse endometrial	137
effects in women who have a uterus.	138
• 	Safety assessments of lipids and of carbohydrate and coagulation parameters	139
(antithrombin III, factor V Leiden, protein-C and protein-S) be conducted.	140
• 	Serum levels of the parent compounds and metabolites be measured.	141
E. 	Primary Endpoints	142
143
For the treatment of moderate to severe vasomotor symptoms, we recommend the following co-	144
primary endpoints:	145
146
• 	Mean change in frequency of moderate to severe vasomotor symptoms from baseline to	147
week 4	148
• 	Mean change in frequency of moderate to severe vasomotor symptoms from baseline to	149
week 12	150
• 	Mean change in severity of moderate to severe vasomotor symptoms from baseline to	151
week 4	152
• 	Mean change in severity of moderate to severe vasomotor symptoms from baseline to	153
week 12	154
155
For the treatment of moderate to severe symptoms of vulvar and vaginal atrophy, we recommend	156
the following co-primary endpoints.	157
158
• 	Mean change from baseline to week 12 in the moderate to severe symptom that has been	159
identified by the patient as being the most bothersome to her	160
• 	Mean change from baseline to week 12 in vaginal pH	161
• 	Mean change from baseline to week 12 in vaginal maturation index (parabasal and	162
superficial cells)	163
F. 	Study Analysis	164
165
For estrogen alone products intended to treat moderate to severe vasomotor symptoms, we	166
recommend that the primary efficacy analyses show a clinically and a statistically significant	167

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reduction, within 4 weeks of initiation of treatment and maintained throughout 12 weeks of	168
treatment, in both the frequency and severity of hot flushes in the treated groups compared with	169
the control groups. Subjective measures (e.g., daily patient diary entries) can be used as primary	170
efficacy endpoints. Alternatively, objective measures (e.g., thermography) can be used both as	171
primary efficacy endpoints and as validation of subjective endpoints. We recommend that study	172
results clearly identify the lowest effective dose of estrogen to support the indication by	173
demonstrating an ineffective lower dose.	174
175
For estrogen alone drug products intended to treat moderate to severe symptoms of vulvar and	176
vaginal atrophy, we recommend that the primary efficacy analyses demonstrate a statistically	177
significant improvement versus placebo from baseline to week 12 of treatment in all three of the	178
following parameters:	179
180
1. 	Maturation Index (decrease of parabasal vaginal cells and increase in superficial	181
vaginal cells)	182
2. 	Lowering of the vaginal pH	183
3. 	The moderate to severe symptom identified by the subject as being most bothersome	184
to her	185
186
187
IV. 	DRUG PRODUCTS CONTAINING ESTROGEN PLUS PROGESTIN	188
189
The approval of specific fixed dose estrogen/progestin drug products for estrogen class labeling	190
indications in women who have a uterus will be based on two criteria: (1) that each component	191
contribute to the efficacy and safety as defined in the combination drug policy (see 21 CFR	192
300.50) and (2) the determination that a combination drug contains the lowest effective dose of	193
each of its active components for their respective labeled indications.	194
195
A. 	Indications	196
197
1. 	Estrogen Component	198
199
The symptomatic indications for estrogen/progestin therapy are the same as those previously	200
discussed under Section III.A of this guidance.	201
202
2. 	Progestin Component	203
204
The progestin component is added to estrogen alone regimens for safety purposes to oppose the	205
adverse effects of estrogen on the endometrium in women who have a uterus. We recommend	206
that sponsors propose low-dose combination estrogen/progestin regimens and dosing schedules	207
that demonstrate endometrial safety and have acceptable endometrial bleeding profiles.	208
209
B. 	Study Considerations	210
211
To support the indication of the treatment of moderate to severe vasomotor symptoms or the	212
treatment of moderate to severe symptoms of vulvar and vaginal atrophy, see Section III.B in	213
this guidance.	214

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215
To demonstrate protection of the endometrium, we recommend that a single, 12-month,	216
randomized, double-blind, dose-ranging phase 3 clinical trial be conducted and include two or	217
more progestin drug treatment arms for each estrogen dose studied. However, the indications in	218
Section III.A can be studied as part of the 12-month endometrial protection study, provided all	219
entrance criteria for each indication are met and the study is powered adequately for each	220
endpoint. We recommend that study results clearly identify the lowest effective dose of estrogen	221
(as described in Section III.B) and the lowest effective dose of progestin to support endometrial	222
safety by demonstrating an ineffective lower dose on the endometrium.	223
224
If the drug to be studied is considered to be a new molecular entity or if it poses unique safety	225
concerns, two placebo-controlled phase 3 clinical trials are recommended to establish safety and	226
efficacy.	227
228
C. 	Inclusion and Exclusion Criteria	229
230
Please refer to the criteria set out in Section III.C., except as specified below.	231
232
We recommend that:	233
234
• 	All subjects have a uterus and have an evaluable screening endometrial biopsy (i.e.,	235
endometrial tissue sufficient for diagnosis). Findings indicating endometrial hyperplasia	236
or cancer would result in exclusion from enrollment and subjects would be referred for	237
standard of care clinical management.	238
• 	A negative screening mammogram (obtained at screening or within 3 months of study	239
enrollment) and normal clinical breast examination be documented prior to enrollment in	240
clinical studies for women > 40 years old. Findings indicating any suspicion of breast	241
malignancy would result in exclusion from enrollment.	242
243
D. 	Monitoring	244
245
We recommend that:	246
247
• 	The endometrial tissue obtained by endometrial biopsy at screening, during the conduct	248
of the study, and at the end-of-study be processed in the same manner by a central	249
laboratory.	250
• 	Endometrial biopsies and not uterine ultrasounds be used for the evaluation of	251
endometrial hyperplasia (sponsors interested in establishing a correlation between	252
transvaginal ultrasound and endometrial biopsy results may perform transvaginal	253
ultrasound immediately preceding endometrial biopsies).	254
• 	A single pathologist reader (any one of the three blinded pathologists) initially assess the	255
slides from the endometrial biopsies obtained at screening or because of participant	256
bleeding while on study drug (safety reading).	257

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• 	For the efficacy evaluation, three independent expert pathologists, blinded to treatment	258
group and to each other’s readings, determine the diagnosis for endometrial biopsy slides	259
during the conduct of the study.	260
• 	Curricula vitae for participating pathologists be provided to the FDA and document	261
expertise in gynecologic pathology.	262
• 	Participating study pathologists be from different institutions with independent fiduciary	263
and organizational reporting, and these pathologists not meet to review slides before or	264
during the conduct of the clinical trial.	265
• 	Standardized criteria as provided in Blaustein’s pathology text (Pathology of the Female	266
Genital Tract) be used for the diagnosis of endometrial hyperplasia (see Appendix for	267
recommended histologic characteristics of the endometrium).	268
• 	Endometrial polyps be fully characterized as to the glandular proliferation and atypia (see	269
Appendix for additional histologic characteristics of the specimen).	270
• 	Subjects found to have endometrial hyperplasia or adenocarcinoma of the endometrium	271
be excluded from further drug treatment (if discovered during study drug treatment	272
period) and referred for standard of care clinical management and followed to complete	273
resolution, and the report of any medical or surgical procedures and the resultant	274
pathology be provided to the FDA.	275
• 	If hyperplasia is diagnosed by the single safety reader for a subject who has bled while on	276
study drug, this diagnosis be maintained for the efficacy evaluation and the slides become	277
part of the slide set given to the two other pathologists for reading.	278
• 	For the efficacy evaluation, the concurrence of two of the three pathologists be accepted	279
as the final diagnosis. If there is no agreement among the three pathologists, the most	280
severe pathologic diagnosis (i.e., atypical hyperplasia > complex hyperplasia > simple	281
hyperplasia > benign endometrium) would be used as the final diagnosis.	282
• 	The slide set distributed to each of the three pathologists for the end-of-study pathology	283
review incorporate control sides representing a randomly selected 10 percent of the	284
screening normal slides and all slides from subjects excluded for the diagnosis of	285
hyperplasia or cancer to insure quality control.	286
• 	Digital recording of diagnostic areas of the slides be maintained by the central laboratory	287
and be made available upon FDA request.	288
• 	Any new findings noted during the conduct of the study and on end-of-study physical	289
examination (including findings related to the breast) receive careful and appropriate	290
evaluation and be monitored until there is complete clinical resolution of any diagnosed	291
condition.	292
• 	Safety assessments of lipids and of carbohydrate and coagulation parameters	293
(antithrombin III, factor V Leiden, protein-C and protein-S) be conducted.	294
• 	Serum levels of the parent compounds and metabolites be measured.	295
296

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E. 	Primary Endpoints	297
298
For protection of the endometrium, we recommend the evaluation of the incidence rate of	299
endometrial hyperplasia at 12 months.	300
301
F. 	Study Analysis	302
303
See Section III.F. for analysis of primary endpoints for treatment of moderate or severe	304
vasomotor symptoms or moderate to severe symptoms of vulvar and vaginal atrophy associated	305
with the menopause. The objective of the clinical trial is to demonstrate the lowest effective	306
dose of the progestin drug that reduces the estimated risk of endometrial hyperplasia after 1 year	307
of estrogen/progestin treatment. The reported 1-year background incidence rate for endometrial	308
hyperplasia in postmenopausal women and in postmenopausal women treated with currently	309
marketed combination estrogen/progestin drugs is approximately 0-1 percent. We recommend	310
that the results from the clinical trial demonstrate a hyperplasia rate that is ≤ 1 percent with an	311
upper bound of the one-sided 95 percent confidence interval for that rate that does not exceed 4	312
percent. The frequency of atypical hyperplasia and cancer are important additional factors to be	313
considered in determining approvability of the drug product. The incidence of hyperplastic	314
polyps and associated atypia would be considered in the safety review.	315
316

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APPENDIX: HISTOLOGIC DESCRIPTIONS RECOMMENDED FOR USE	317
WHEN READING ENDOMETRIAL BIOPSY SLIDES	318
319
320
321
Histologic Characteristics of the Endometrium	322
323
0. 	No tissue	324
325
1. 	Tissue insufficient for diagnosis	326
327
2. 	Atrophic	328
329
3. 	Inactive	330
331
4. 	Proliferative	332
333
a. Weakly proliferative	334
335
b. Active proliferative	336
337
c. Disordered proliferative	338
339
5. 	Secretory	340
341
a. Cyclic type	342
343
b. Progestational type (including stromal decidualization)	344
345
6. 	Menstrual type	346
347
7. 	Simple hyperplasia without atypia	348
349
8. 	Simple hyperplasia with atypia	350
351
9. 	Complex hyperplasia without atypia	352
353
10. Complex hyperplasia with atypia	354
355
11. Carcinoma (specify type)	356
357

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358
Additional Histologic Characteristics	359
360
If there are any polyps, please specify the type or types.	361
362
Functional	363
Atrophic	364
Hyperplastic without atypia	365
Hyperplastic with atypia	366
Carcinomatous	367
368
If there is any stromal tissue, please specify the type or types.	369
370
Smooth muscle tissue, normal	371
Features suggestive of adenomyoma	372
Features suggestive of stromal nodule	373
Sarcoma (specify type)	374
375
If there is any metaplasia, please specify the type or types.	376
377
Squamous	378
Papillary	379
Eosinophilic	380
Ciliated	381
Mucinous	382
Syncytial	383
Other type (specify type)	384
385
If there is any cervical tissue, please specify the type or types.	386
387
Fragments of negative cervical epithelium	388
Endocervical polyp	389
Atypical endocervical glandular epithelium	390
Atypical squamous metaplasia	391
Squamous dysplasia	392
Cervical carcinoma	393
394
395