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DRAFT GUIDANCE 
This guidance document is being distributed for comment purposes only.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of  publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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
07/01/19  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 FEATURESKEY 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 
2  Hormonal Drug Products Intended to 
3  Prevent Pregnancy1 
4   
5   
6   
7  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
8  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
9  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
10  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
11  for this guidance as listed on the title page. 
12   
13   
14   
15  I.  INTRODUCTION 
16   
17  This guidance provides recommendations for clinical trials designed to establish clinical 
18  effectiveness and safety for hormonal drug products intended to prevent pregnancy2. Drug 
19  product development in hormonal contraception has evolved over the years, especially with 
20  the development of lower-dose hormonal drug products and longer-acting reversible 
21  contraceptives. Changes in patient demographics, pregnancy testing, determinations of 
22  conception date, and dosing directions have also occurred. This guidance reflects these 
23  developments and is generally consistent with advice we have been providing to individual 
24  sponsors developing hormonal drug products.  
25   
26  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
27  Instead, guidances describe the Agencys current thinking on a topic and should be viewed 
28  only as recommendations, unless specific regulatory or statutory requirements are cited.  The 
29  use of the word should in Agency guidances means that something is suggested or 
30  recommended, but not required. 
31   
32   
33  II.  CLINICAL TRIAL DESIGN FEATURESKEY CONSIDERATIONS 
34   
35  A.  Recommended Enrollment Criteria 
36   
37  Nonpregnant, premenopausal women who meet the following criteria are eligible for enrollment: 
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.  
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
39    Have normal, regular menstrual cycles that are between 21 and 35 days in 
40  duration 
41   
42    Engage in regular heterosexual vaginal intercourse (at least once per month) with 
43  a partner who is not known to be subfertile or infertile  
44   
45    Have no evidence of dysplasia or invasive cervical cancer on screening per 
46  current guidelines  
47   
48    Have adequate washout of other contraceptives (e.g., resumption of regular 
49  menses after long-acting contraceptives and contraceptives that alter the 
50  menstrual cycle) 
51   
52    Are agreeable to not using other contraceptives or other methodology to prevent 
53  pregnancy during the trial 
54   
55    Have no history of infertility  
56   
57  The effectiveness of some contraceptives may be reduced with increasing body weight. Sponsors 
58  should not place restrictions on body mass index (BMI) for trial enrollment. The trial population 
59  should include obese women (i.e., defined as BMI of at least 30 kg/m2), and the analysis plan 
60  should include a prespecified subgroup efficacy analysis in this population. Insufficient data in 
61  the obese population may result in a limitation of use for this population in labeling. During the 
62  trial design phase, sponsors should discuss with the division the adequacy of the number of 
63  cycles of drug exposure that will be derived from obese subjects.  
64   
65  Enrollment of subjects older than 35 years old is recommended for safety determinations. The 
66  number of subjects older than 35 years old who should be enrolled in the trial or trials will 
67  depend on the existing experience with the drug product ingredients and should be discussed 
68  with the division.  
69   
70  Trials should include subjects from all premenopausal age groups who are likely to use the drug 
71  product, including postmenarchal adolescents.  
72   
73  B.  Study Elements 
74   
75  Randomizing subjects to placebo is not feasible because subjects in a contraceptive trial do not 
76  desire pregnancy. Approximately 80% to 90% of women of reproductive potential who use no 
77  contraception and engage in regular intercourse are expected to become pregnant within 1 year 
78  (Guttmacher 1956; Zinaman et al. 1996; Wang et al. 2003; Gnoth et al. 2003; Slama et al. 2012), 
79  and contraceptives typically have sizeable treatment effects. Therefore, single-arm, open-label, 
80  historically controlled trials are generally sufficient to establish efficacy. Sponsors should discuss 
81  with the division how they intend to ensure an accurate assessment of contraceptive 
82  effectiveness, such as minimizing missing data and minimizing premature subject 
83  discontinuation.  
84   
2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
85  In some instances, it may be possible to conduct a single phase 3 trial (e.g., for combined 
86  estrogen and progestin products). In other instances, two phase 3 trials may be recommended 
87  (e.g., a novel contraceptive drug product). Sponsors should discuss with the division the number 
88  of trials appropriate for the drug product. 
89   
90  Data from single-arm, open-label trials of at least 1 years duration are generally sufficient to 
91  establish efficacy and safety, provided that the trials are well-conducted. Trials of longer 
92  duration (covering the maximum duration of use proposed in labeling) are recommended for 
93  long-acting reversible contraceptives, such as intrauterine systems. Trials of shorter duration may 
94  be sufficient for products containing drug substances that already have well-characterized safety 
95  profiles. Sponsors should discuss the adequacy of the trial duration with the division. 
96   
97  For a new molecular entity (NME), the division recommends that total drug product exposure 
98  include at least 20,000 menstrual cycles, with at least 400 subjects who complete the trial or 
99  trials. For a non-NME for which one or more clinical trials are needed, the division recommends 
100  that total drug product exposure should include at least 10,000 menstrual cycles, with at least 200 
101  subjects who complete the trial or trials.  
102   
103  Subjects should complete a daily diary that adequately captures whether vaginal intercourse 
104  occurred, the use of backup and emergency contraceptive methods, and bleeding and/or spotting 
105  patterns. We encourage the use of an electronic diary (ediary). 
106   
107  Urine pregnancy tests should be performed regularly at clinic visits, including at the end of the 
108  study or with premature subject discontinuation. Sponsors should provide subjects with home 
109  pregnancy test kits for use in case of signs and symptoms of pregnancy or multiple missed 
110  contraceptive doses. A positive urine pregnancy test (whether conducted at home or in the clinic) 
111  should be confirmed by serum testing and, if positive, an ultrasonography should be performed 
112  for dating. Sponsors should discuss the number and timing of clinic visits with the division. 
113   
114  Other important considerations during development of drug products intended to prevent 
115  pregnancy include the following: 
116   
117    Pregnancy outcomes should be collected and reported. 
118   
119    Early discussion with the division is particularly encouraged for products with novel 
120  delivery systems or device components. 
121   
122    Sponsors are encouraged to conduct lactation studies for new drug products or dosing 
123  regimens, as women often want to restart contraception during the postpartum period.  
124   
125  C.  Efficacy Considerations 
126   
127  On-treatment pregnancy should be defined as any pregnancy that occurs during use of the 
128  product or within a specific timeframe after last use of the product. Some examples are provided 
129  below. Sponsors should discuss with the division the appropriate timeframe after last use for 
130  other scenarios.  
3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
131   
132  For contraceptives that require daily administration (e.g., oral combined hormonal 
133  contraceptives), last use includes the use of the product from the placebo (or drug-free days) or 
134  estrogen-only phase of the regimen. A positive pregnancy test within 7 days of this last use 
135  would be considered on-treatment (a detected pregnancy in this timeframe reflects conception 
136  that occurred when pregnancy should still have been prevented). For example, if a womans 
137  estimated date of conception is 7 days after she completed Day 28 of a 21/7 (active/placebo) 
138  regimen, a positive pregnancy test would be considered on-treatment. 
139   
140  For long-acting injectable contraceptives (e.g., medroxyprogesterone acetate), a positive 
141  pregnancy test after the last dosing and prior to the next scheduled dose would be considered on-
142  treatment. 
143   
144  For an intrauterine system (IUS), a positive pregnancy test within 7 days after IUS removal 
145  would be considered on-treatment (a detected pregnancy in this timeframe reflects conception 
146  that occurred while the IUS was still in place).  
147   
148  The primary efficacy endpoint should be the pregnancy rate described by the Pearl Index (PI) 
149  during the first year of use of the product. The PI is defined as the number of pregnancies per 
150  100 woman-years and is calculated as follows:  
151   
152   
153   
NNNNNNNNNNNN oooo ppNNNNppppppppppppNNpp13 ppccppccNNpp
154   
PPPP = 100
155    NNNNNNNNNNNN oo2oo8  -day  ppccppccNNpp pppp ddNNooppppNNdd NNNNccoobb
156  Calculation of the PI for the primary efficacy evaluation should include only cycles during which 
157  (a) vaginal intercourse occurred and (b) no backup or emergency contraception was used based 
158  on diary data.  
159   
160  Life table analysis should also be used as a supportive analysis to provide monthly and 
161  cumulative failure rates for any specific length of exposure and will be included in labeling for 
162  long-acting contraceptive products that are evaluated in trials of more than 1 years duration. 
163   
164  The assessment of efficacy is based on the point estimate and the upper bound of the 
165  corresponding 95% confidence interval for the PI. Combined hormonal contraceptives are very 
166  effective at preventing pregnancy, typically having an upper bound of this 95% confidence 
167  interval below 5 in adequately designed and conducted trials. For hormonal contraceptives with 
168  fewer risks, such as oral progestin-only contraceptives, a slightly higher upper bound of this 95% 
169  confidence interval may be acceptable. 
170   
171  The primary efficacy results should be calculated using the trial population of women younger 
172  than or equal to 35 years old at study enrollment because the likelihood of pregnancy decreases 
173  with advancing age. Include additional efficacy analyses for the overall trial population and a 
174  subgroup analysis for those older than 35 years old.  
175   
4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
176  For the overall trial population, as well as for those younger than or equal to 35 years old at study 
177  enrollment and those older than 35 years old, sponsors should perform subgroup analyses based 
178  on BMI at study enrollment and geographic region (United States and Canada versus rest of the 
179  world). 
180   
181  Efficacy results can differ considerably between countries and may be related to factors that 
182  impact the single-arm, open-label trial results (e.g., treatment adherence, body weight, and 
183  smoking). When there are apparent differences in efficacy results across geographic regions, the 
184  labeled efficacy results will be solely based on data from cycles derived from study sites in the 
185  United States and Canada to provide efficacy data that is pertinent to the overall United States 
186  population.  
187   
188  D.  Safety Considerations 
189   
190  The safety evaluation should include data from all enrolled subjects (from all participating 
191  countries), including those older than and younger than 35 years old.  
192   
193  Hormonal contraceptives have well-known risks, some of which are infrequent, such as venous 
194  thromboembolism. The division may require postmarketing evaluation of risks such as venous 
195  thromboembolism if the benefits of a new drug product outweigh its risks, but additional 
196  characterization of the risk is required postapproval.  
197     
5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
198  REFERENCES 
199   
200  Gnoth C, D Godehardt, E Godehardt, P Frank-Herrmann, and G. Freundl, 2003, Time to 
201  Pregnancy: Results of the German Prospective Study and Impact on the Management of 
202  Infertility, Hum Reprod, 18(9):19591966. 
203   
204  Guttmacher AF, 1956, Factors Affecting Normal Expectancy of Conception, J Am Med Assoc, 
205  161(9):855860. 
206   
207  Slama R, OKH Hansen, B Ducot, A Bohet, D Sorensen, L Giorgis Allemand, MJC Eijkemans, L 
208  Rosetta, JC Thalabard, N. Keiding, and J Bouyer, 2012, Estimation of the Frequency of 
209  Involuntary Infertility on a Nation-Wide Basis. Hum Reprod. 27(5):14891498. 
210   
211  Wang X, C Chen, L Wang, D Chen, W. Guang, and J. French, 2003, Conception, Early 
212  Pregnancy Loss, and Time to Clinical Pregnancy: A Population-Based Prospective Study, Fertil 
213  Steril, 79(3):577584. 
214   
215  Zinaman MJ, ED Clegg, CC Brown, J OConnor, and SG Selevan, 1996, Estimates of Human 
216  Fertility and Pregnancy Loss, Fertil Steril, 65(3):503509. 
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