Establishing Effectiveness and Safety for Hormonal Drug Products Intended to Prevent Pregnancy Guidance for Industry

Administrative draft guidance, not enacted legislation.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

07/01/19
Establishing Effectiveness and
Safety for Hormonal Drug
Products Intended to Prevent
Pregnancy
Guidance for Industry
DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.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of publication in the Federal Register of the notice announcing the availability of the draft
guidance.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 electronic comments to https://www.regulations.gov. Submit written
comments to the Dockets Management Staff (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 regarding this draft document, contact Jennifer Mercier at 301-796-0957.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research
(CDER)
July 2019
Clinical/Medical

Establishing Effectiveness and
Safety for Hormonal Drug
Products Intended to Prevent
Pregnancy
Guidance for Industry
Additional copies are available from:
Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: druginfo@fda.hhs.gov
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
July 2019
Clinical/Medical

TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	CLINICAL TRIAL DESIGN FEATURES—KEY CONSIDERATIONS .................. 1
A. 	Recommended Enrollment Criteria ............................................................................................. 1
B. 	Study Elements ............................................................................................................................... 2
C. 	Efficacy Considerations ................................................................................................................. 3
D. 	Safety Considerations .................................................................................................................... 5
REFERENCES.............................................................................................................................. 6

Contains Nonbinding Recommendations
Draft — Not for Implementation
1
Establishing Effectiveness and Safety for	1
Hormonal Drug Products Intended to	2
Prevent Pregnancy1
3
4
5
6
This draft guidance, when finalized, will represent the current thinking of the Food and Drug	7
Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not	8
binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the	9
applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible	10
for this guidance as listed on the title page.	11
12
13
14
I. 	INTRODUCTION	15
16
This guidance provides recommendations for clinical trials designed to establish clinical	17
effectiveness and safety for hormonal drug products intended to prevent pregnancy2. Drug	18
product development in hormonal contraception has evolved over the years, especially with	19
the development of lower-dose hormonal drug products and longer-acting reversible	20
contraceptives. Changes in patient demographics, pregnancy testing, determinations of	21
conception date, and dosing directions have also occurred. This guidance reflects these	22
developments and is generally consistent with advice we have been providing to individual	23
sponsors developing hormonal drug products.	24
25
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.	26
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed	27
only as recommendations, unless specific regulatory or statutory requirements are cited. The	28
use of the word should in Agency guidances means that something is suggested or	29
recommended, but not required.	30
31
32
II. 	CLINICAL TRIAL DESIGN FEATURES—KEY CONSIDERATIONS	33
34
A. 	Recommended Enrollment Criteria	35
36
Nonpregnant, premenopausal women who meet the following criteria are eligible for enrollment:	37
38
1 This guidance has been prepared by the Division of Bone, Reproductive, and Urologic Products in the Center for
Drug Evaluation and Research at the Food and Drug Administration.
2 This guidance does not provide development information on nonhormonal contraception or emergency
contraception.

Contains Nonbinding Recommendations
Draft — Not for Implementation
2
• 	Have normal, regular menstrual cycles that are between 21 and 35 days in	39
duration	40
41
• 	Engage in regular heterosexual vaginal intercourse (at least once per month) with	42
a partner who is not known to be subfertile or infertile	43
44
• 	Have no evidence of dysplasia or invasive cervical cancer on screening per	45
current guidelines	46
47
• 	Have adequate washout of other contraceptives (e.g., resumption of regular	48
menses after long-acting contraceptives and contraceptives that alter the	49
menstrual cycle)	50
51
• 	Are agreeable to not using other contraceptives or other methodology to prevent	52
pregnancy during the trial	53
54
• 	Have no history of infertility	55
56
The effectiveness of some contraceptives may be reduced with increasing body weight. Sponsors	57
should not place restrictions on body mass index (BMI) for trial enrollment. The trial population	58
should include obese women (i.e., defined as BMI of at least 30 kg/m2 ), and the analysis plan	59
should include a prespecified subgroup efficacy analysis in this population. Insufficient data in	60
the obese population may result in a limitation of use for this population in labeling. During the	61
trial design phase, sponsors should discuss with the division the adequacy of the number of	62
cycles of drug exposure that will be derived from obese subjects.	63
64
Enrollment of subjects older than 35 years old is recommended for safety determinations. The	65
number of subjects older than 35 years old who should be enrolled in the trial or trials will	66
depend on the existing experience with the drug product ingredients and should be discussed	67
with the division.	68
69
Trials should include subjects from all premenopausal age groups who are likely to use the drug	70
product, including postmenarchal adolescents.	71
72
B. 	Study Elements	73
74
Randomizing subjects to placebo is not feasible because subjects in a contraceptive trial do not	75
desire pregnancy. Approximately 80% to 90% of women of reproductive potential who use no	76
contraception and engage in regular intercourse are expected to become pregnant within 1 year	77
(Guttmacher 1956; Zinaman et al. 1996; Wang et al. 2003; Gnoth et al. 2003; Slama et al. 2012),	78
and contraceptives typically have sizeable treatment effects. Therefore, single-arm, open-label,	79
historically controlled trials are generally sufficient to establish efficacy. Sponsors should discuss	80
with the division how they intend to ensure an accurate assessment of contraceptive	81
effectiveness, such as minimizing missing data and minimizing premature subject	82
discontinuation.	83
84

Contains Nonbinding Recommendations
Draft — Not for Implementation
3
In some instances, it may be possible to conduct a single phase 3 trial (e.g., for combined	85
estrogen and progestin products). In other instances, two phase 3 trials may be recommended	86
(e.g., a novel contraceptive drug product). Sponsors should discuss with the division the number	87
of trials appropriate for the drug product.	88
89
Data from single-arm, open-label trials of at least 1 year’s duration are generally sufficient to	90
establish efficacy and safety, provided that the trials are well-conducted. Trials of longer	91
duration (covering the maximum duration of use proposed in labeling) are recommended for	92
long-acting reversible contraceptives, such as intrauterine systems. Trials of shorter duration may	93
be sufficient for products containing drug substances that already have well-characterized safety	94
profiles. Sponsors should discuss the adequacy of the trial duration with the division.	95
96
For a new molecular entity (NME), the division recommends that total drug product exposure	97
include at least 20,000 menstrual cycles, with at least 400 subjects who complete the trial or	98
trials. For a non-NME for which one or more clinical trials are needed, the division recommends	99
that total drug product exposure should include at least 10,000 menstrual cycles, with at least 200	100
subjects who complete the trial or trials.	101
102
Subjects should complete a daily diary that adequately captures whether vaginal intercourse	103
occurred, the use of backup and emergency contraceptive methods, and bleeding and/or spotting	104
patterns. We encourage the use of an electronic diary (ediary).	105
106
Urine pregnancy tests should be performed regularly at clinic visits, including at the end of the	107
study or with premature subject discontinuation. Sponsors should provide subjects with home	108
pregnancy test kits for use in case of signs and symptoms of pregnancy or multiple missed	109
contraceptive doses. A positive urine pregnancy test (whether conducted at home or in the clinic)	110
should be confirmed by serum testing and, if positive, an ultrasonography should be performed	111
for dating. Sponsors should discuss the number and timing of clinic visits with the division.	112
113
Other important considerations during development of drug products intended to prevent	114
pregnancy include the following:	115
116
• 	Pregnancy outcomes should be collected and reported.	117
118
• 	Early discussion with the division is particularly encouraged for products with novel	119
delivery systems or device components.	120
121
• 	Sponsors are encouraged to conduct lactation studies for new drug products or dosing	122
regimens, as women often want to restart contraception during the postpartum period.	123
124
C. 	Efficacy Considerations	125
126
On-treatment pregnancy should be defined as any pregnancy that occurs during use of the	127
product or within a specific timeframe after last use of the product. Some examples are provided	128
below. Sponsors should discuss with the division the appropriate timeframe after last use for	129
other scenarios.	130

Contains Nonbinding Recommendations
Draft — Not for Implementation
4
131
For contraceptives that require daily administration (e.g., oral combined hormonal	132
contraceptives), last use includes the use of the product from the placebo (or drug-free days) or	133
estrogen-only phase of the regimen. A positive pregnancy test within 7 days of this last use	134
would be considered on-treatment (a detected pregnancy in this timeframe reflects conception	135
that occurred when pregnancy should still have been prevented). For example, if a woman’s	136
estimated date of conception is 7 days after she completed Day 28 of a 21/7 (active/placebo)	137
regimen, a positive pregnancy test would be considered on-treatment.	138
139
For long-acting injectable contraceptives (e.g., medroxyprogesterone acetate), a positive	140
pregnancy test after the last dosing and prior to the next scheduled dose would be considered on-	141
treatment.	142
143
For an intrauterine system (IUS), a positive pregnancy test within 7 days after IUS removal	144
would be considered on-treatment (a detected pregnancy in this timeframe reflects conception	145
that occurred while the IUS was still in place).	146
147
The primary efficacy endpoint should be the pregnancy rate described by the Pearl Index (PI)	148
during the first year of use of the product. The PI is defined as the number of pregnancies per	149
100 woman-years and is calculated as follows:	150
151
152
𝑃𝑃𝑃𝑃 = 𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝑝𝑝𝑁𝑁𝑁𝑁𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑁𝑁𝑝𝑝 × 13 𝑝𝑝𝑐𝑐𝑝𝑝𝑐𝑐𝑁𝑁𝑝𝑝
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜
28-day 𝑝𝑝𝑐𝑐𝑝𝑝𝑐𝑐𝑁𝑁𝑝𝑝 𝑝𝑝𝑝𝑝 𝑑𝑑𝑁𝑁𝑜𝑜𝑝𝑝𝑝𝑝𝑁𝑁𝑑𝑑 𝑁𝑁𝑁𝑁𝑐𝑐𝑜𝑜𝑏𝑏 × 100	153
154
155
Calculation of the PI for the primary efficacy evaluation should include only cycles during which	156
(a) vaginal intercourse occurred and (b) no backup or emergency contraception was used based	157
on diary data.	158
159
Life table analysis should also be used as a supportive analysis to provide monthly and	160
cumulative failure rates for any specific length of exposure and will be included in labeling for	161
long-acting contraceptive products that are evaluated in trials of more than 1 year’s duration.	162
163
The assessment of efficacy is based on the point estimate and the upper bound of the	164
corresponding 95% confidence interval for the PI. Combined hormonal contraceptives are very	165
effective at preventing pregnancy, typically having an upper bound of this 95% confidence	166
interval below 5 in adequately designed and conducted trials. For hormonal contraceptives with	167
fewer risks, such as oral progestin-only contraceptives, a slightly higher upper bound of this 95%	168
confidence interval may be acceptable.	169
170
The primary efficacy results should be calculated using the trial population of women younger	171
than or equal to 35 years old at study enrollment because the likelihood of pregnancy decreases	172
with advancing age. Include additional efficacy analyses for the overall trial population and a	173
subgroup analysis for those older than 35 years old.	174
175

Contains Nonbinding Recommendations
Draft — Not for Implementation
5
For the overall trial population, as well as for those younger than or equal to 35 years old at study	176
enrollment and those older than 35 years old, sponsors should perform subgroup analyses based	177
on BMI at study enrollment and geographic region (United States and Canada versus rest of the	178
world).	179
180
Efficacy results can differ considerably between countries and may be related to factors that	181
impact the single-arm, open-label trial results (e.g., treatment adherence, body weight, and	182
smoking). When there are apparent differences in efficacy results across geographic regions, the	183
labeled efficacy results will be solely based on data from cycles derived from study sites in the	184
United States and Canada to provide efficacy data that is pertinent to the overall United States	185
population.	186
187
D. 	Safety Considerations	188
189
The safety evaluation should include data from all enrolled subjects (from all participating	190
countries), including those older than and younger than 35 years old.	191
192
Hormonal contraceptives have well-known risks, some of which are infrequent, such as venous	193
thromboembolism. The division may require postmarketing evaluation of risks such as venous	194
thromboembolism if the benefits of a new drug product outweigh its risks, but additional	195
characterization of the risk is required postapproval.	196
197

Contains Nonbinding Recommendations
Draft — Not for Implementation
6
REFERENCES	198
199
Gnoth C, D Godehardt, E Godehardt, P Frank-Herrmann, and G. Freundl, 2003, Time to	200
Pregnancy: Results of the German Prospective Study and Impact on the Management of	201
Infertility, Hum Reprod, 18(9):1959–1966.	202
203
Guttmacher AF, 1956, Factors Affecting Normal Expectancy of Conception, J Am Med Assoc,	204
161(9):855–860.	205
206
Slama R, OKH Hansen, B Ducot, A Bohet, D Sorensen, L Giorgis Allemand, MJC Eijkemans, L	207
Rosetta, JC Thalabard, N. Keiding, and J Bouyer, 2012, Estimation of the Frequency of	208
Involuntary Infertility on a Nation-Wide Basis. Hum Reprod. 27(5):1489–1498.	209
210
Wang X, C Chen, L Wang, D Chen, W. Guang, and J. French, 2003, Conception, Early	211
Pregnancy Loss, and Time to Clinical Pregnancy: A Population-Based Prospective Study, Fertil	212
Steril, 79(3):577–584.	213
214
Zinaman MJ, ED Clegg, CC Brown, J O’Connor, and SG Selevan, 1996, Estimates of Human	215
Fertility and Pregnancy Loss, Fertil Steril, 65(3):503–509.	216