From The Advisory Committee For Reproductive Health Drugs

Advisory Committee for Reproductive Health Drugs
Ulipristal acetate 30 mg tablet
June 17, 2010 Briefing Materials
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HRA Pharma Advisory Committee for Reproductive Health Drugs
Ulipristal acetate 30 mg tablet June 17, 2010 Briefing Materials
Table of Contents
1 EXECUTIVE SUMMARY ............................................................................................................11
2 INTRODUCTION ..........................................................................................................................19
3 EMERGENCY CONTRACEPTION: THE NEED FOR NEW TREATMENT OPTIONS ..20
3.1 Key points ................................................................................................................................ 20
3.2 Unintended pregnancy: a public health challenge ................................................................... 20
3.2.1 Contraception practice...................................................................................................... 20
3.2.2 High rates of unintended pregnancies .............................................................................. 21
3.2.3 Contraceptive discontinuation .......................................................................................... 22
3.2.4 Contraceptive failures ...................................................................................................... 22
3.2.5 Estimating the need for emergency contraception ........................................................... 23
3.3 History of emergency contraception and available methods ................................................... 24
3.4 Need for additional treatment options ..................................................................................... 25
4 ULIPRISTAL ACETATE PRODUCT RATIONALE ............................................................28

4.1 Key points ................................................................................................................................ 28
4.2 Product background ................................................................................................................. 28
4.3 Overview of development program ......................................................................................... 30
4.3.1 Nonclinical studies ........................................................................................................... 30
4.3.2 Clinical studies ................................................................................................................. 30
4.4 Regulatory history ................................................................................................................... 31
4.4.1 Interactions with FDA ...................................................................................................... 31
4.4.2 Foreign approvals ............................................................................................................. 33
4.5 Preclinical overview ................................................................................................................ 33
4.5.1 Primary Pharmacology ..................................................................................................... 33
4.5.2 Safety pharmacology ........................................................................................................ 37

May 2010 Page 2 of 108
4.5.3 Pharmacokinetics ............................................................................................................. 37
4.5.4 Toxicology ....................................................................................................................... 38
4.6 Clinical Pharmacology & Mechanism of Action .................................................................... 41
4.7 Rationale for dose determination ............................................................................................. 45
4.8 Overview of efficacy trials ...................................................................................................... 45
4.8.1 Methods of efficacy trials ................................................................................................. 46
4.8.2 Rationale for the choice of clinical thresholds ................................................................. 49
4.8.3 Methods of pooled efficacy analysis ................................................................................ 49
5 CLINICAL EFFICACY ................................................................................................................51

5.1 Key points ................................................................................................................................ 51
5.2 Summary of results from supportive efficacy trials (Phase 2/3 studies) ................................. 51
5.2.1 Study 507.......................................................................................................................... 51
5.2.2 Study 508.......................................................................................................................... 52
5.3 Disposition and demographics in Phase 3 studies ................................................................... 54
5.4 Primary efficacy results ........................................................................................................... 58
5.5 Additional efficacy analyses .................................................................................................... 59
5.5.1 Efficacy over time ............................................................................................................ 59
5.5.2 Comparative efficacy vs. levonorgestrel .......................................................................... 60
5.5.3 Efficacy in population subgroups and per intrinsic or extrinsic factors ........................... 62
5.6 Generalizability of efficacy data.............................................................................................. 63
6 CLINICAL SAFETY .....................................................................................................................65

6.1 Key points ................................................................................................................................ 65
6.2 Exposure to ulipristal acetate ................................................................................................... 65
6.2.1 Sources of information and overall extent of exposure.................................................... 65
6.2.2 Collection and analysis of safety data .............................................................................. 67

6.3 Safety from single dose exposure ............................................................................................ 69
6.3.1 Serious adverse events ..................................................................................................... 69
6.3.2 Individual study results .................................................................................................... 71
6.3.3 Pooled safety analyses ...................................................................................................... 78
6.4 Safety profile from repeated dose exposure ............................................................................ 80
6.4.1 Repeated dose Study 510 ................................................................................................. 80
6.4.2 Multiple enrollments in efficacy emergency contraception trials repeat use ................ 81
6.5 Drug interactions ..................................................................................................................... 81
6.6 Post-marketing safety experience ............................................................................................ 81
6.7 Pregnancy ................................................................................................................................ 82
6.8 Safety conclusions ................................................................................................................... 84
7 BENEFIT/RISK ASSESSMENT & CONCLUSIONS ...............................................................86

8 REFERENCES ...............................................................................................................................88
9 APPENDICES ................................................................................................................................94
Table of Tables
Table 1 Summary of primary efficacy ................................................................................................... 15
Table 2 Demography on contraceptive use in the US (Source: Mosher et al, 2004) ............................. 21
Table 3 Failure rate of contraceptive methods in perfect or typical use (Source: Ranjit et al, 2001) .... 23
Table 4 Summary of key agreements on Phase 3 program with FDA from SPA .................................. 33
Table 5 In vivo hormonal activity of ulipristal acetate (Study 404) ....................................................... 35
Table 6 Inhibition of ovulation by a single oral dose of ulipristal acetate administered to rats on the day
of proestrus (Study 405) ......................................................................................................................... 35
Table 7 Post-coital activity of ulipristal acetate in rats and rabbits ....................................................... 36
Table 8 Safety pharmacology profile of ulipristal acetate ..................................................................... 37

Table 9 Repeated-dose and reproductive toxicology studies with ulipristal acetate.............................. 38
Table 10 Reproductive and developmental toxicity of ulipristal acetate given during day 0 to day 3 of
gestation in the rat .................................................................................................................................. 40
Table 11 Reproductive and developmental toxicity of ulipristal acetate given from day 6 of gestation
through to weaning in the rat.................................................................................................................. 41
Table 12 Effect of ulipristal acetate administered (when lead follicle is 14-16 mm) on time to follicular
collapse (Study 505) ............................................................................................................................... 42
Table 13 Inhibition of follicular rupture with ulipristal acetate dosing when leading follicle is 18 mm
(Study 511) ............................................................................................................................................. 43
Table 14 Overview of design of efficacy studies ................................................................................... 46
Table 15 Statistical methods of NICHD supportive Phase 2/3 efficacy trials ....................................... 47
Table 16 Statistical methods of HRA Pharma pivotal Phase 3 efficacy trials ....................................... 48
Table 17 Summary description of pooled efficacy analyses .................................................................. 49
Table 18 Study 507: pregnancy rates ..................................................................................................... 52
Table 19 Study 508: pregnancy rates ..................................................................................................... 53
Table 20 Demographics of Study 509 population (n=1533) .................................................................. 55
Table 21 Demographics of Study 513 population .................................................................................. 57
Table 22 Study 509: Comparison of observed vs. expected pregnancy rates ........................................ 58
Table 23 Study 513: Comparison of observed vs. expected pregnancy rates ........................................ 59
Table 24 Studies 509 and 513: Pregnancy rates by time from unprotected intercourse to ulipristal
acetate treatment ..................................................................................................................................... 59
Table 25 Pooled Phase 3 studies: Pregnancy rates by time from unprotected intercourse to ulipristal
acetate treatment ..................................................................................................................................... 60
Table 26 Study 513: Comparative pregnancy rates for treatment within 72 h or 120 h of unprotected
intercourse .............................................................................................................................................. 61
Table 27 Laboratory evaluations performed during clinical development of ulipristal acetate ............. 68
Table 28 Serious Adverse Events reported in subjects administered single dose ulipristal acetate, with
causality assessment ............................................................................................................................... 69

Table 29 Ultrasound findings recorded as ovarian cysts during Phase 1 studies with ulipristal acetate 71
Table 30 Pregnancies and outcome, in Study 507 ................................................................................. 72
Table 32 Incidence of Adverse Events in 1% of ITT population subjects in Study 509 .................... 74
Table 33 Duration of treatment cycle in ITT population of Study 509.................................................. 75
Table 35 Incidence of Adverse Events in 1% of ITT population subjects in Study 513 .................... 76
Table 36 Duration of treatment cycle in ITT population of Study 513.................................................. 77
Table 38 Incidence of Adverse Events in 1% of ITT pooled Phase 3 population subjects reported
between inclusion and end of the study (approximately one month) ..................................................... 79
Table 39 Duration of treatment cycle in subjects who did not become pregnant, in the ITT pooled
Phase 3 population (first participation only) .......................................................................................... 79
Table 40 Endometrial histology following 10 weeks of daily ulipristal acetate, in Study 510 ............. 81
Table 41 Pregnancies and outcome, in clinical development program for EC ...................................... 83
Table 42 Pregnancies and outcome in post-marketing surveillance of ellaOne ................................... 84
Table 43: Tabular listing of all clinical studies ...................................................................................... 95
Table 44 Demographics of the Study 507 population ............................................................................ 98
Table 45 Demographics of the Study 508 population ............................................................................ 99
Table 46 Pregnancy rates observed and expected after ulipristal acetate treatment according to intrinsic
factors (pooled Phase 3 population) ..................................................................................................... 101
Table 47 Pregnancy rates observed and expected after ulipristal acetate treatment for each subgroup
population and extrinsic factor (pooled Phase 3 population) ............................................................... 102
Table 48 Number of subjects exposed to ulipristal acetate (single dose administration) during clinical
studies in EC......................................................................................................................................... 103
Table 49 Adverse Event frequencies and most common Adverse Events in Phase 1 studies, single
administration ....................................................................................................................................... 104

Table 50 Summary of laboratory tests findings in Phase 1 studies, single administration .................. 104
Table 51 Incidence of Adverse Events in 1% of ITT population subjects, in Study 507 ................. 105
Table 52 Incidence of Adverse Events in 1% of ITT population subjects, in Study 508 ................. 106
Table 53 Demographics of the pooled Phase 3 safety population ....................................................... 107
Table 54 Incidence (in %) of Adverse Events in 1% of pooled Phase 3 safety population subjects
according to age, geographical region and BMI .................................................................................. 108
according to race .................................................................................................................................. 108
Table of Figures
Figure 1 Development program ............................................................................................................. 14
Figure 2 Structure of ulipristal acetate in comparison to progesterone.................................................. 19
Figure 3 Contraceptive prevalence among women at risk and unintended pregnancies in the US ....... 22
Figure 4 Pregnancy rate of levonorgestrel EC according to time elapsed between unprotected

intercourse and treatment (Source: von Hertzen et al. 1998) ................................................................. 26
Figure 5 Inhibition of follicular rupture for at least 5 days after treatment with 0.75-mg levonorgestrel
twice, 12h apart, or placebo (Source: Croxatto et al. 2004) ................................................................... 26
Figure 6 Probability of conception according to cycle day relative to ovulation (=0): the fertile
window (Source: Trussell et al. 1998) ................................................................................................. 27
Figure 7 Frequency of intercourse relative to ovulation (the fertile window in grey) (Source: Wilcox et
al. 2004) .................................................................................................................................................. 27
Figure 8 Overlay of progesterone receptor ligand binding domain with ulipristal acetate (yellow) or
progesterone (turquoise) ......................................................................................................................... 29
Figure 9 Key interactions with FDA ...................................................................................................... 32
Figure 10 Inhibition of follicular rupture at 5 days after treatment stratified by LH status at the time of
treatment (Study 511) ............................................................................................................................. 43

Figure 11 LH levels after dosing (Tx) either before the onset of the LH surge (left panel), after the
onset of the LH surge but before the LH peak (middle panel), or after the LH peak (right panel) (Study
511)......................................................................................................................................................... 44
Figure 12 Study 507: Disposition of subjects ........................................................................................ 52
Figure 16 Adjusted odds ratio of pregnancy with ulipristal acetate compared to levonorgestrel (OR and
95% CI) in individual studies and for meta-analysis ............................................................................ 61
Figure 17 Number of subjects exposed to single dose of ulipristal acetate during the clinical
development in EC ................................................................................................................................. 66
Figure 18 Most frequent Adverse Events (3% of ITT population subjects), in Study 513 ................. 77
Table of Appendices
Appendix 1 List of clinical studies ...................................................................................................... 95
Appendix 2 Demographics of Phase 2/3 study populations ................................................................ 98
Appendix 3 Efficacy subgroup analyses ........................................................................................... 101
Appendix 4 Single dose safety exposure........................................................................................... 103
Appendix 5 Safety results from Phase 1 studies (single dose administration).................................. 104
Appendix 6 Safety results from Phase 2/3 studies (507, 508) .......................................................... 105
Appendix 7 Demographics of the pooled Phase 3 safety population ................................................ 107
Appendix 8 - Subgroup safety analyses ............................................................................................... 108

LIST OF ABBREVIATIONS
ACTH Adrenocorticotropic Hormone

AE Adverse Event
ALAT Alanine aminotransferase
ALP Alkaline phosphatise
ALT Alanine transaminase
AST Aspartate transaminase
ATC Anatomical Therapeutic Chemical
AUC Area under the curve
BMI Body mass index
CBC Complete blood count
CDB Contraceptive Development Branch
CI Confidence interval
Cmax Maximum concentration
CPK Creatine phosphokinase
CYP Cytochrome P450
Fixed difference or fixed margin
DNA Deoxyribonucleic acid
DSMB Data safety monitoring board
EC Emergency contraception
ECG Electrocardiogram
EE population Efficacy evaluable population
E(PR) Expected pregnancy rate in absence of contraception
FDA Food and Drug Administration
FSH Follicle stimulating hormone
GD Gestation day
GGT Gamma-glutamyl transpeptidase
GI Gastro-intestinal
GLP Good laboratory practice
hCG Human chorionic gonadotropin
HDL High-density lipoprotein
HERG Human ether-a-go-go gene
H0 Null hypothesis
H1 Alternative hypothesis
ICH International Conference on Harmonisation
IND Investigational New Drug Application
ITT population Intent-To-Treat population
IUD Intra-uterine device
LC-MS/MS Liquid chromatography tandem mass spectrometry
LD Lactation day

LDL Low-density lipoprotein

LH Luteinizing hormone
LNG Levonorgestrel
MedDRA Medical Dictionary for Regulatory Affairs
mITT Modified Intent-To-Treat
NDA New Drug Application
NADPH Nicotinamide adenine dinucleotide phosphate
NICHD National Institute of Child Health and Human Development
NOEL No observed effect level
p.c. Post coitum
p.o. Per-os
OR Odds ratio
OTC Over the counter
True pregnancy rate
pUPA Observed pregnancy rate in UPA group
pLEV Observed pregnancy rate in LNG group
PD Pharmacodynamics
PK Pharmacokinetics
PR Progesterone receptor
PR Pregnancy rate (used in efficacy results)
PSUR Periodic Safety Update Report
RIA Radio-immunoassay
RTI Research Triangle Institute
Rx Under prescription
SAE Serious adverse event
SD Standard deviation
SPA Special Protocol Assessment
SPRM Selective progesterone receptor modulator
TSH Thyroid-stimulating hormone
Tx Treatment
UL95%CI Upper Limit of the 95% Confidence Interval
UM Unmicronized
UPA Ulipristal acetate
UPI Unprotected intercourse
WHO World Health Organization

May 2010 Page 10 of 108
1 EXECUTIVE SUMMARY
Introduction
New Drug Application (NDA) 22-454 was submitted by HRA Pharma on October 15, 2009 to request
approval for ulipristal acetate, a selective progesterone receptor modulator, as an emergency
contraceptive indicated for the prevention of pregnancy following unprotected intercourse or a known
or suspected contraceptive failure. The proposed trade name for the product is ella.
The proposed dosing regimen is one 30-mg tablet taken orally as soon as possible within 120 hours
(5 days) after unprotected intercourse or a known or suspected contraceptive failure. As a method of
emergency contraception (EC), ulipristal acetate is not intended for routine use as a contraceptive.
The application summarized data from 13 clinical studies including four efficacy trials in which over
4,000 women at risk of pregnancy from unprotected sexual intercourse or failure of a contraceptive
method received ulipristal acetate for EC. These data support the following conclusions:
- ulipristal acetate reduces pregnancy risk when used up to 120 h after intercourse
- ulipristal acetate has a well-characterized safety profile, with the most frequently reported
adverse events (headache, nausea, dysmenorrhea and abdominal pain) being those commonly
reported in studies of EC and similar to those described for approved products
- ulipristal acetate would offer women and healthcare professionals an important new treatment
option for reducing the risk of unintended pregnancy.
Unmet Need and Limitations of Current Methods
Unintended pregnancy is a major public health problem; it is associated with an increased risk of
morbidity for women, and with health behaviors during pregnancy, such as delay in prenatal care, that
are associated with adverse outcomes. There are about 3 million unintended pregnancies each year in
the US. Just over half of these occur among women who are using a regular method of contraception.
Sometimes, a woman needs a backup contraceptive method when her regular method fails a condom
breaks, a diaphragm slips, a woman forgets to take her pill. Intercourse can also be unplanned or
unwanted. Emergency contraception, which prevents pregnancy after unprotected sexual intercourse,
provides a second chance to women who find themselves at risk of unintended pregnancy.
EC is defined as the use of a drug or device as an emergency measure to prevent pregnancy after
unprotected intercourse. Intercourse that occurs on days that fall in the fertile window (the six days
leading up to and including the day of ovulation) may lead to fertilization. As the lifespan of sperm in
the female genital tract is estimated at five days, women who recognize that they may be at risk of an
unintended pregnancy within five days of intercourse are therefore candidates for EC. As for all
methods of contraception, EC is not indicated for use in pregnant women.

May 2010 Page 11 of 108
Current utilization of EC falls far short of the estimated potential need when compared to the
frequency of unprotected sex among couples who are not actively seeking pregnancy. The absence of
any products specifically packaged, labeled, and marketed as an emergency contraceptive was for
many years a major obstacle to more widespread use. Even though high doses of combined oral
contraceptives were prescribed off-label for EC starting in the late 1970s (the Yuzpe method),
nearly forty years elapsed between the first FDA approval for hormonal contraception in 1960 and the
introduction of the first product labeled for EC in 1998. The FDA was instrumental in encouraging the
introduction of registered products, having issued a statement in the Federal Register in 1997 that
emergency contraceptive pills were safe and effective in preventing pregnancy after sex.
The progestin levonorgestrel at a dose of 1.5 mg is the only drug currently marketed in the US for EC,
with two dosage forms available: a single dose of 1.5 mg (Plan B One-Step) or two 0.75-mg doses to
be taken 12 h apart (Plan B or Next Choice). Levonorgestrel was approved for EC by the FDA in
1999 for Rx marketing and was subsequently switched to OTC status with an age restriction (OTC
approved in 2006 for women 18 and over, and in 2009 for 17 and over).
Levonorgestrel is indicated for use within 72 h (3 days) following unprotected intercourse or a known
or suspected contraceptive failure, and FDA-approved labeling stipulates that efficacy is better if the
tablet is taken as soon as possible after unprotected intercourse. Indeed in multiple clinical trials the
efficacy of levonorgestrel has been seen to decline with time after sexual intercourse, and available
evidence indicates only limited effectiveness beyond 72h. For a woman who presents for EC more
than 72 h after intercourse, the only available method with proven efficacy is the insertion of a copper
intra-uterine device (although not approved or labeled for such use in the US), but use is limited by
both availability and the need for insertion by a health-care professional. There remains an unmet need
for an approved, easy to use oral therapy that is consistently effective for longer than 72 h after
intercourse, encompassing the time that sperm can survive in the female genital tract.
Since the Yuzpe method of high dose combined oral contraceptives was described more than 30 years
ago, understanding of the mechanism of action of hormonal EC has gradually grown but remains
limited. Multiple mechanisms of action have been evoked, including disruption of the ovulatory
process, interference with tubal transport of sperm and/or ova and endometrial alteration. The best-
documented mechanism for approved levonorgestrel products is blockade or delay of ovulation via
shunting of the LH surge. However, the ability of levonorgestrel to interfere with the ovulatory process
is limited to its administration during the period preceding the onset of the LH surge. Once the
ovulatory process has been triggered by the LH surge, this progestin agent does not prevent the follicle
from rupturing and releasing the oocyte, an event that normally takes place 36 h later. A compound
that can consistently prevent or delay ovulation, regardless of how late in the follicular phase it is
given, would be a more effective method of EC than levonorgestrel.

May 2010 Page 12 of 108
Ulipristal Acetate Background
Progesterone plays a pivotal role in reproduction in many species. It is involved in the control of
ovulation, implantation, and maintenance of pregnancy. Progesterone mediates its physiological
effects through interaction with the progesterone receptor, a member of the superfamily of nuclear
receptors. The recognition of the important role of progesterone in reproduction led to the development
of synthetic progesterone receptor ligands, also known as selective progesterone receptor modulators.
Ulipristal acetate is a selective progesterone receptor modulator that is a derivative of 19-nor-
progesterone and the first compound of the -pristal class. The requested indication for EC is the first
NDA for this new molecular entity which is also under evaluation with daily or continuous dosing for
regular contraception as well as the treatment of benign and malignant gynecological disorders
including uterine fibroids, endometriosis and breast cancer.
Also known as CDB-2914, ulipristal acetate was originally synthesized by Research Triangle Institute
(RTI) under contract with the National Institute of Child Health and Human Development (NICHD).
NICHD carried out the initial preclinical and clinical development of the compound until HRA Pharma
licensed-in the molecule in 2000 and took over its development. A Collaborative Research and
Development Agreement between NICHD and HRA Pharma signed in 2002 and renewed in 2006
provides for shared access to research results as well as collaboration on further product development.
Ulipristal acetate has potent affinity for the progesterone receptor (PR) and in in vitro models inhibits
endogenous PR-mediated enzyme and transcriptional activity. Its effects would appear to be
differentially mediated in the two different PR isoforms A and B, providing evidence of a mixed
agonist-antagonist profile. A series of in vivo animal studies provide evidence that ulipristal acetate
inhibits glandular proliferation in the uterine lining, inhibits ovulation and prevents pregnancy when
administered post-coitally.
A complete battery of nonclinical safety studies, including safety pharmacology, toxicology,

reproductive toxicity and genotoxicity, complemented by pharmacokinetic studies, produced findings
consistent with the disruption of the hypothalamic-pituitary-adrenal axis and reproductive system that
would be expected from a progesterone receptor modulator. No findings suggested a safety risk when
administered as an emergency contraceptive.
Clinical Development Program
Based on nonclinical evidence that ulipristal acetate inhibits ovulation and is a potent orally-active
post-coital contraceptive in animals, a clinical development program was undertaken for EC (Figure
1). As summarized in the below figure, this program consisted of:
- four pharmacodynamic studies designed to evaluate the effect of ulipristal acetate on

folliculogenesis, ovulation and endometrial maturation when administered as single doses at
different times in the menstrual cycle

May 2010 Page 13 of 108
- a broad Phase 2/3 efficacy and dose-determination program sponsored by NICHD
- two pivotal Phase 3 efficacy studies sponsored by HRA Pharma.
Additional pharmacokinetic studies were also performed to characterize the absorption profile of the
various dosage forms used throughout the development program.
Figure 1 Development program
Pharmacodynamics
The effect of single doses of ulipristal acetate on ovarian function and cycle parameters was evaluated
in four pharmacodynamic studies in healthy female volunteers. In the initial three studies sponsored by
NICHD, single doses ranging from 10 to 200 mg were administered at different phases in the
menstrual cycle (mid-luteal, mid-follicular or early luteal phase). When administered to women at the
mid-luteal phase (Study 503), no significant effect on menstrual cycle length was observed at doses up
to 100 mg. However, women receiving a single 200-mg dose all had a shortened luteal phase and early
menses. Mid-follicular administration (Study 505) slowed follicular growth and delayed ovulation in
all dose groups (10, 50 or 100 mg), and early luteal administration (Study 506) increased glandular
progesterone receptor expression at the higher doses tested (50 and 100 mg) without affecting
endometrial maturation, luteolysis or menstrual cycle length.
A more recent study (Study 511) evaluated the effect of a single 30-mg dose (to-be marketed tablet)
taken immediately before ovulation (when follicular rupture is imminent), and showed a potent
inhibitory effect on follicular rupture in a majority of cycles for more than five days after treatment,
even when given after the onset of the LH surge. This means that ulipristal acetate could prevent
pregnancy by delaying ovulation when administered very late in the follicular phase, even if LH levels
have already began to rise, a time when levonorgestrel EC no longer appears to inhibit follicular
rupture. Since sperm can survive up to five days in the female genital tract, the longer ovulation can be
delayed, the lower the likelihood of fertilization. This enhanced ability to inhibit ovulation is a good
predictor that ulipristal acetate should be a highly effective method of EC.

May 2010 Page 14 of 108
Clinical Trials for Emergency Contraception
Methods
The efficacy and safety of ulipristal acetate for prevention of pregnancy as EC was evaluated in a
large-scale program including four studies and over 6,000 women enrolled at study sites in the US and
Europe. Studies conducted by NICHD utilized unmicronized ulipristal acetate while studies conducted
by HRA Pharma utilized reformulated, micronized ulipristal acetate in delivery-matched doses.
In all four efficacy trials, women were eligible for enrollment if they presented to a participating
family planning center requesting EC within 5 days following unprotected intercourse or contraceptive
failure, if they had regular menstrual cycles and a negative high sensitivity urine pregnancy test.
Eligibility criteria were purposefully left as broad as possible to allow inclusion of a representative
study population, with lower age limits (16 or 18 years) applied according to local and national
regulations on age of majority for informed consent.
To determine the efficacy outcome (pregnancy or no pregnancy), systematic pregnancy testing was
performed at clinic follow-up, scheduled approximately one week after expected onset of next menses
after enrollment. EC being a coitus-specific method, the classical Pearl index for measuring
contraceptive efficacy is not appropriate for use. The primary efficacy endpoint in the four efficacy
trials was the pregnancy rate (PR) in the study population, and the primary results are summarized in
Table 1.
Table 1 Summary of primary efficacy
Study # 507 508 509 513

Primary Is the difference in PR Is the difference in PR Is PR of UPA 30-mg Is PR of UPA 30-mg
question between UPA 50-mg and between UPA 10-mg and inferior to expected PR inferior to expected PR
of interest LNG when taken within 50-mg when taken (in the absence of (in the absence of
72 h of unprotected within 72 h of contraception) and contraception) and
intercourse smaller than unprotected intercourse inferior to clinical inferior to clinical
the unacceptable margin smaller than the interest limit of 4% interest limit of 4%
of 2% in points? unacceptable margin of when taken 48 to 120 h when taken within 72 h
2.5% in points? of unprotected of unprotected
intercourse? intercourse?
Main Positive Negative Positive Positive
outcome
PR: pregnancy rate
Phase 2/3 Comparative Efficacy and Dose-Ranging
The NICHD-sponsored efficacy program included two double-blind Phase 2/3 studies performed
entirely in the US: the first one (Study 507) compared a single 50-mg dose of unmicronized ulipristal
acetate with two 0.75-mg doses of levonorgestrel in 1,578 women, and the second one (Study 508),
compared 10- vs. 50-mg ulipristal acetate in 749 women. Both studies employed a non-inferiority

May 2010 Page 15 of 108
design, and both enrolled women who presented within 72 h of unprotected intercourse or a
contraceptive failure.
The results showed that:
- the primary efficacy analysis of Study 507 was positive. The observed pregnancy rates for
ulipristal acetate (0.9%, 95% CI: 0.2-1.6%) when taken within 72 h of intercourse was smaller
than that of levonorgestrel (1.7%, 95% CI: 0.8-2.6%);
- the primary efficacy analysis of Study 508 based on non-inferiority of ulipristal acetate 10 mg
versus 50 mg was negative. The observed pregnancy rate of ulipristal acetate 10 mg (2.7%,
95% CI: 1.3-5.0%) when taken within 72 h of intercourse was twice as large than that of 50 mg
(1.3%, 95% CI: 0.4-3.0%).
Phase 3 Pivotal Efficacy Trials
The Phase 3 pivotal program, sponsored by HRA Pharma and conducted in accordance with FDA
recommendations obtained via a Special Protocol Assessment (SPA), consisted of two large-scale
studies. Both studies evaluated a 30-mg dose of ulipristal acetate in the micronized tablet formulation
that is the dosage form proposed for marketing. The objective of the Phase 3 program was to provide
statistical evidence that ulipristal acetate is effective for EC up to 120 h after intercourse, and in both
trials the primary efficacy analysis was a comparison of the observed pregnancy rate (point estimate
and 95% CI) in the study population having received EC versus the pregnancy rate expected in the
absence of any intervention for EC. For the studies to be considered a success, in addition to this
comparison being conclusive, the upper bound of the 95% CI around the pregnancy rate had to be less
than a clinical interest limit set at 4%.
The first study (Study 509) was a single-arm open-label study performed in the US that evaluated the
efficacy of ulipristal acetate in 1,241 women who took it for EC 48 to 120 h after intercourse. The
second study (Study 513) was a randomized, controlled, single-blind, non-inferiority study that
evaluated the efficacy of ulipristal acetate in comparison with levonorgestrel 1.5 mg in 1,899 women
in the US and in Europe. In this trial, women who presented up to 120 h after unprotected intercourse
were eligible for enrollment, and the primary efficacy analysis was performed as specified in the
protocol in the subgroup of women who presented within 72 h (n=1,694).

May 2010 Page 16 of 108
The main results of the Phase 3 program are as follows:
- the primary efficacy analysis of Study 509 was positive: in women treated 48-120 h after
intercourse in Study 509 (n=1,241), the overall pregnancy rate was 2.10% (95% CI: 1.41%,
3.10%), which was significantly lower than the expected pregnancy rate in the study population
(5.53%) and below the clinical interest limit (4%)
- the primary efficacy analysis of Study 513 was positive: in women treated with ulipristal
acetate 0-72h after intercourse in Study 513 (n=843), the overall pregnancy rate was 1.78%
(95% CI: 1.04%, 2.98%), which was significantly lower than the expected pregnancy rate in
that same group (5.54%) and below the clinical interest limit (4%); in comparison, in women
treated with levonorgestrel during the same time window (n=851), the overall pregnancy rate
was 2.59% (95% CI: 1.68%, 3.94%)
- ulipristal acetate was consistently effective up to 120 h after unprotected intercourse, with no
significant time-related trend in efficacy observed in either Phase 3 trial or in the pooled
analysis of the two trials.
The total dataset for ulipristal acetate treatment more than 72 h after unprotected intercourse in the
Phase 3 program counts 648 women, significantly more than in published reports with other
emergency contraceptives.
In both of the efficacy trials that included a levonorgestrel comparison group (Studies 507 and 513),
ulipristal acetate was associated with a lower pregnancy rate than levonorgestrel. To assess consistency
across trials, the datasets from these two trials were pooled via an exploratory meta-analysis and
pregnancy rates compared via logistic regression. The results showed that in comparison with
levonorgestrel, ulipristal acetate significantly reduced the risk of becoming pregnant in women who
received EC, whether used within 72 h (OR 0.58, 95% CI: 0.33-0.99) or 24 h (OR 0.35, 95% CI: 0.11-
0.93) of unprotected sexual intercourse.
Clinical Safety
In the course of the clinical development program, over 4,700 women were exposed to ulipristal
acetate, including some 2,700 women who received the to-be-marketed 30-mg formulation. In
addition, single doses up to 200 mg and continuous dosing of up to 10 mg/day for twelve weeks were
evaluated in Phase 1 trials in healthy women volunteers.
Laboratory safety evaluations of biochemical and hematological parameters were carried out in eight
PK/PD trials and in a subset of subjects enrolled in one of the Phase 3 trials. In all PD trials, blood
samples to assess hypothalamo-pituitary-ovarian axis were taken. Menstrual cycle length and bleeding
patterns were recorded in several Phase 1 studies and all four efficacy trials. In the efficacy trials,
subjects were asked to record adverse events (AEs) in home diaries.

May 2010 Page 17 of 108
Adverse events reported during the development program were for the most part mild to moderate in
severity. The most frequently reported AEs were headache, nausea, dysmenorrhea and abdominal pain,
a profile similar to that of approved emergency contraceptive products. No serious unexpected adverse
reactions were reported. Laboratory safety parameters were measured in a subset of subjects. Changes
detected after treatment were few and sporadic and do not suggest a specific treatment effect.
Ulipristal acetate treatment slightly increased menstrual cycle length (median of +1 day in Phase 3
studies) but women reported normal menses duration. Intermenstrual bleeding, mostly limited to
spotting, was reported in 8.7% of subjects in Phase 3 studies. Subsequent menstrual cycles were
normal.
Women who received ulipristal acetate repeatedly by re-enrolling in the Phase 3 trials (in different
menstrual cycles as permitted by protocol) did not experience AEs different in incidence or severity
than others, nor was the duration or volume of menstrual bleeding or the incidence of inter-menstrual
bleeding after ulipristal acetate different.
As of May 12, 2010, reports of 111 pregnancies in women exposed to ulipristal acetate have been
collected in clinical trials (n=93) or via post-marketing surveillance (n=18). No ectopic pregnancies
have been reported. Pregnancies that were observed during clinical trials of ulipristal acetate ended in
elective termination in almost two-thirds of the cases. Few pregnancies were carried to term. In
comparative studies, the rates of spontaneous miscarriage observed were similar between the ulipristal
acetate and levonorgestrel arms.
Exploratory analyses did not detect any differences in the safety profile according to age, geographical
region, race, BMI category, concomitant medication use or repeated exposure to ulipristal acetate.
Conclusions
As demonstrated by data from an extensive development program, ulipristal acetate administered at a

dose of 30 mg is an effective method of EC when used up to 120 h after unprotected intercourse or
failure of a contraceptive method. The data included in the submission for ulipristal acetate constitute
the only conclusive demonstration of emergency contraceptive efficacy for any hormonal product
when taken more than 72 h after intercourse. The available safety database on this new molecular
entity is extensive, and without signals that would suggest particular safety risks.
The federal government has continually recognized the contribution of family planning and
reproductive health to the well-being of Americans, and in 2000, the US Department of Health and
Human Services set a national goal of decreasing unintended pregnancies from 50% in 2001 to 30% by
2010. Although use of EC will always depend on the ability of women to recognize the risk of
unintended pregnancy, an orally active method that is effective up to five days after intercourse would
provide women a valuable second chance. Ulipristal acetate therefore has the potential to become an
important new treatment for reproductive health care in the public health arsenal.

May 2010 Page 18 of 108
2 INTRODUCTION
New Drug Application 22-454 was submitted by HRA Pharma on October 15, 2009 to request
approval for ulipristal acetate as an emergency contraceptive indicated for the prevention of pregnancy
following unprotected intercourse or a known or suspected contraceptive failure. The proposed dosing
regimen is one 30-mg tablet taken orally as soon as possible within 120 hours (5 days) after
unprotected intercourse or a known or suspected contraceptive failure. Ulipristal acetate is a method of
emergency contraception, and is not intended for routine use as a contraceptive.
Ulipristal acetate (17-Acetoxy-11-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-

dione) is a derivative of 19-norprogesterone that binds with high affinity to the progesterone receptor
(Figure 2). A new molecular entity, it is the first member of a new pharmacological class of selective
progesterone receptor modulators (SPRMs) designated by the pristal suffix.
Figure 2 Structure of ulipristal acetate in comparison to progesterone
CH3
H3C N
H3C H3C
O O
CH3 CH3
O C CH3
CH3
O
O O
Progesterone Ulipristal acetate
The basis for filing is a comprehensive quality, nonclinical and clinical development program that
spans 13 clinical trials including four efficacy trials in over 6,000 women. In 2006, the FDA agreed
that, under the Special Protocol Assessment procedure, the planned design and analyses of two pivotal
efficacy trials sponsored by HRA Pharma were acceptable (Section 4.4).
Both pivotal trials were conclusive with respect to the protocol definition of study success, and the
data submitted in the NDA support the following conclusions:
1. Ulipristal acetate significantly reduces pregnancy risk when used up to 120 hours after
unprotected intercourse or a contraceptive failure.
2. Ulipristal acetate has a well-characterized safety profile. The most frequently reported AEs
(headache, nausea, dysmenorrhea and abdominal pain) are commonly reported in studies of
emergency contraceptives and are similar to those described for approved products.
3. Ulipristal acetate would offer women and healthcare professionals an important new treatment
option for reducing the risk of unintended pregnancy.

May 2010 Page 19 of 108
3 EMERGENCY CONTRACEPTION: THE NEED FOR NEW TREATMENT

OPTIONS
3.1 Key points
Despite widespread use of effective methods of contraception, half of the pregnancies that occur
every year in the United States are unintended.
Emergency contraception complements ongoing methods of contraception in that it provides a

back-up solution that can be used post-coitally by women who find themselves at risk of
unintended pregnancy after unprotected intercourse or a contraceptive failure.
The efficacy of currently-marketed emergency contraceptive products (levonorgestrel) declines

rapidly as time goes by after intercourse, and hence they are not labeled for use after 72 h.
Levonorgestrel inhibits ovulation only if it is administered before the onset of the LH surge, and
therefore is not effective if administered just prior to ovulation at the time when intercourse is most
likely to result in conception.
There is therefore an unmet need for a method of emergency contraception that is consistently
effective over several days after intercourse and at the height of the fertile window.
3.2 Unintended pregnancy: a public health challenge
3.2.1 Contraception practice
The introduction of approved methods of contraception in the 1960s allowed women to gain control
over their own fertility for the first time. These methods, particularly the birth control pill, achieved
widespread use in the US (U.S. Department of Health, Education, and Welfare), resulting in high
contraceptive coverage, which is considered by the Centers for Disease Control and Prevention to be
one of the ten most significant US public health achievements of the 20th century (Centers for Disease
Control and Prevention, 1999).
According to the last National Survey of Family Growth conducted in 2002, 62% of the 61.6 million
women aged 1544 in the US currently use contraceptives (Mosher et al, 2004). The majority of
women who use contraceptives rely on very effective methods: 28% are sterilized, 2% have an intra-
uterine device and 31% use oral contraception, a proportion that has remained stable over the past
20 years. Another 11.8% of American women use barrier contraceptives, mostly the male condom
(94%). The choice of method varies throughout life and follows the prevailing contraceptive norm,
which supports the use of condoms at sexual initiation, followed by the pill once in a stable
relationship, and ending in sterilization, the leading method of contraception once the desired family
size is achieved. Patterns of contraceptive use also vary according to womens socio-economic status.

May 2010 Page 20 of 108
Table 2 Demography on contraceptive use in the US (Source: Mosher et al, 2004)
Number of women
%
(in millions)
Women 15-44 years 61.6 100
Women 15-44 years at-risk 42.7 69.4
Contraceptive users 15-44 years 38.2 62
Contraceptive non users 15-44 years 23 38
Women at risk and who do not use contraception 15- 44 years 4.3 7.4
3.2.2 High rates of unintended pregnancies
Despite the widespread use of very effective methods, one in every two women aged 15-44 in the US
has experienced at least one unintended pregnancy (Jones et al, 2006). There were 3.1 million
unintended pregnancies in 2001 alone, accounting for 49% of all pregnancies (Finer et al, 2006), and
there has been little change since the mid 1990s (Henshaw et al, 1998). These statistics have resulted
in a national health objective being generated to increase the proportion of pregnancies that are
intended in Healthy People 2010 (U.S. Department of Health and Human Services, 2000). Forty eight
percent of unintended pregnancies are terminated by abortions, which represents 22% of all
pregnancies in the US (Jones et al, 2008). Abortion rates have declined since 1991, mostly due to a
sharp reduction in teenage abortion rates during 1990s (Jones et al, 2008). However, after 15 years of
steady decline, a 5% increase in teenage birth rates was recorded between 2005 and 2007 (Hamilton et
al, 2009). This is of particular concern as it appears to be related to a decline in contraceptive use
among the youngest generation (Santelli et al, 2010). Pregnancy rates among American teenagers,
which are mostly unintended (Finer et al, 2006), remain the highest of all industrialized countries
(Santelli et al, 2010).
The three most important factors that contribute to the high rate of unintended pregnancies are the lack
of or discontinuation of contraceptive use, high contraceptive failure rates and the use of less effective
methods (Mishell et al, 1999).

May 2010 Page 21 of 108
3.2.3 Contraceptive discontinuation
Women who are at risk and do not use contraception account for a disproportionate number of
unintended pregnancies, as they account for 52% of all unintended pregnancies (Figure 3).
Figure 3 Contraceptive prevalence among women at risk and unintended pregnancies in the US
Left: proportion of contraception users (light blue) and non-users (dark blue)
Right: proportion of unintended pregnancies among contraception users (light blue) and non-users (dark blue)
100%
11%
75%
50%
25%
89%
0%
No contraception Contraception No contraception Contraception
Neither contraceptive use nor the level of risk is static. Data from the 1995 National Survey of Family
Growth estimate that the typical woman who uses reversible methods of contraception continuously
from her 15th to her 45th birthday will discontinue contraception nearly ten times for method-related
reasons (Trussell et al, 1993). In a 2002 survey, almost half of the women had stopped their
contraceptive method, including the pill, by the end of the first 12 months, even though they were still
in need of contraception (Trussell et al, 1999). While the vast majority resume contraceptive use
shortly after discontinuing their previous method (Trussell et al, 1999), the transition period leaves
women exposed to unintended pregnancy. These results are unsettling, especially since studies
focusing on pill users suggest that a significant proportion switch to less effective methods or to no
method at all (Rosenberg et al, 1995). Each year, nearly one in four American women who are at risk
of unintended pregnancy discontinues contraceptive use for one or more months (Frost et al, 2008).
3.2.4 Contraceptive failures
As shown in Figure 3, if half of unintended pregnancies result from a lack of contraceptive use, the
other half (48.5%) are due to contraceptive failure (Finer et al, 2006). These pregnancies occur not
only in women who rely on barrier or natural methods of contraception but also result from failures
using very effective methods, especially oral contraceptives which require adherence to a prescribed
schedule (Finer et al, 2006). These data reflect the difficulties that women experience in their daily use
of contraception and this translates into a gap between failure rates during perfect use and during
typical use. Failure rates during typical use are higher at the start of use, which links back to the

May 2010 Page 22 of 108
problem of contraceptive discontinuation (including method switching) as a significant contributor to

unintended pregnancies (Ranjit et al, 2001) (Table 3).
Table 3 Failure rate of contraceptive methods in perfect or typical use (Source: Ranjit et al, 2001)
Perfect use Typical use

US
Pill 0.3 8.7
IUD 0.1-1.5 -
Condom 2 17.4
Withdrawal 4 18.8
Spermicides, sponges 8 29
Fertility awareness 25.3
Overall 1.4 12.4
3.2.5 Estimating the need for emergency contraception
In the context of the current situation in the US, emergency contraception offers an important option to
reduce the risk of becoming accidentally pregnant and help women achieve their reproductive goals.
Emergency contraception is defined as the use of a drug or device as an emergency measure to prevent
pregnancy after unprotected intercourse (Cheng et al, 2008). Intercourse that occurs on days that fall in
the fertile window (the six days leading up to and including the day of ovulation) may lead to
fertilization (Wilcox et al, 2000). The lifespan of sperm in the female genital tract is estimated at five
days (Gould et al, 1984), women who recognize that they may be at risk of an unintended pregnancy
within five days of intercourse are candidates for emergency contraception.
Different approaches are used to estimate the need for emergency contraception. One way is to study
women who have actually been at risk because they have experienced an unintended pregnancy. Based
on contraceptive failure rates during perfect use and typical use in the US, researchers from the
Guttmacher Institute have estimated that half of unintended pregnancies occur among women who
were not using contraception in the month they conceived and another 43% occurred among women
who used their method inconsistently * (Finer et al, 2006). Surveys of women seeking pregnancy
termination in the US provide evidence of a large unmet need for contraceptive backup. Results from a
national survey conducted in 2000-2001, among 10,683 women, show that nearly half (46.8%) of these
women were not using contraception at the time that they became pregnant, while 46.9% became
pregnant because of inconsistent or incorrect contraceptive use (Jones et al, 2002). Both of these
situations are appropriate indications for emergency contraception as a back-up option to reduce the
risk of unintended pregnancies. However, only 1.3% of women seeking to terminate their pregnancy
had used emergency contraception to try to avoid becoming pregnant. Misperception of pregnancy risk
is a leading reason for not using contraception, indeed, 33% of patients seeking abortions perceived
themselves to be at low risk of pregnancy. Other reasons included concerns about contraceptive
methods (32%), unexpected sex (26%) and sexual violence (1%).

May 2010 Page 23 of 108
Not all women become pregnant following an act of unprotected intercourse. Therefore the need for
backup contraception should be estimated among all couples of reproductive age who are not actively
trying to become pregnant and not only among those who suffer the consequences of unprotected
intercourse. Based on the distribution of contraceptive use among women who are at risk and the
frequency of sexual intercourse in the general population, it is estimated that approximately 1 million
acts of unprotected intercourse occur each day in the US. Results from a national probability survey of
1,978 women aged 1844 at risk of unintended pregnancy indicate that over a one-year period, half
were adequately protected from unintended pregnancy, 8% did not use contraception all year, 15%
experienced gaps in their use of contraception and 27% reported inconsistent use (Frost et al, 2008).
Nearly two-fifths of women using the pill and three fifths of women using condom admitted to using
their method inconsistently in the three months prior to the study (Frost et al, 2008).
3.3 History of emergency contraception and available methods
The roots of emergency contraception date to the 1920s, when researchers first demonstrated that
estrogenic ovarian extracts interfere with pregnancy in mammals (Haspels et al, 1994). Veterinarians
were the first to apply this finding, administering estrogens to dogs and to horses that had mated when
their owner had not wanted them to, and the first documented cases of human use were published in
the mid-1960s when physicians in the Netherlands applied the veterinary practice of postcoital
estrogen administration to a 13-year-old girl who had been raped at midcycle (Ellertson, 1996).
At around the same time, US researchers were investigating the efficacy of high-dose estrogens, and
toward the end of the decade, these preparations became the standard. In the early 1970s, the high-dose
estrogen regimens gave way to a combined estrogen-progestin standard. Canadian physician Albert
Yuzpe and his colleagues began studies in 1972 on this combined regimen, and the "Yuzpe method,"
as it came to be known, replaced high-dose estrogen formulations, chiefly because it offered a lower
incidence of side effects (Yuzpe et al, 1974). The late 1970s also saw the emergence of the chief non-
hormonal method available today, the copper-releasing IUD.
Research on non-estrogenic methods of post-coital contraception began in the 1970s in Latin America
and led to the registration of levonorgestrel as an ongoing post-coital contraceptive in Eastern Europe
in the early 1980s: Doses of levonorgestrel ranging from 0.15 to 1 mg and taken within 3 h after sexual
intercourse were used, and in 1980 a 0.75-mg tablet (Postinor) was approved in Hungary for use within
a maximum of 1 h after coitus (Seregely et al, 1982), (ADIS R&D Profile, 2002). Such research came
to a head in the context of a World Health Organization-sponsored program that provided evidence in
two randomized controlled trials published in 1993 (Ho et al, 1993) and 1998 (WHO Task Force),
respectively, that a regimen consisting of two doses of 0.75-mg levonorgestrel, 12 h apart, was an
effective method of emergency contraception for use up to 72 h after unprotected sexual intercourse
and was associated with lower incidence of nausea and vomiting than the Yuzpe method. Subsequent
trials showed that a single 1.5-mg dose of levonorgestrel was as effective as the split-dose regimen
(von Hertzen et al, 2002), (Arowojolu et al, 2002). Levonorgestrel at the dose of 1.5 mg (administered

May 2010 Page 24 of 108
either in a single dose or as two 0.75-mg doses 12 h apart) is the current standard of care for
emergency contraception within 72 h of unprotected intercourse or contraceptive failure.
Despite the considerable evidence regarding hormonal regimens for emergency contraception available
in the published literature starting in the 1970s, such methods remained doctors secret recipe for
nearly three decades (Hatcher et al, 1995). It was not until after a 1996 meeting of FDAs
Reproductive Health Drugs Advisory Committee reached the unanimous conclusion that certain oral
contraceptives are safe and effective for use in an emergency postcoital regimen that for the first time a
pharmaceutical company came forward with an application for a dedicated product. Preven, a
combined estrogen-progestin emergency contraceptive, was approved for marketing in 1998 but has
since been removed from the market. Currently marketed in the US under the brands Plan B, Plan B
One-Step (Teva) and Next Choice (Watson Pharmaceuticals), levonorgestrel was approved in 1999
for prescription (Rx) marketing for women of fertile age and was subsequently switched to Over-The-
Counter (OTC) status with an age restriction (OTC approved in 2006 for women 18 and over, and in
2009 for 17 and over).
3.4 Need for additional treatment options
Today, a decade after the introduction of dedicated emergency contraceptive products in the US,
widespread use of the method remains a challenge. Numerous clinical trials have shown that
facilitating access to emergency contraception (by providing advance supplies or allowing OTC
access) increases its use, without negatively affecting sexual behaviors or regular contraceptive use
(Polis et al, 2007). Nevertheless, current use of emergency contraception falls far short of its potential
need for it. In 2003, only 6% of US women aged 18 to 49 had ever used it (Cheng et al, 2008).
Emergency contraception has proven efficacy in reducing an individual womans risk of becoming
pregnant (Cheng et al, 2008). Its public health impact has yet to be demonstrated due to the fact that
this method is used in only a small minority of potential usage occasions following unprotected
intercourse (Raymond et al, 2007). Unperceived pregnancy risk and concerns about side effects are
some of the reasons why women may decide not use emergency contraception (Polis et al, 2007) -
(Raymond et al, 2007). The rapid change in access to emergency contraception may paradoxically
have helped contribute to this situation. Indeed, by taking away the role of physicians as emergency
contraception prescribers, their level of investment in counseling and sexual health may have been
reduced (The Kaiser Family Foundation, 2003 and 2004).
Levonorgestrel, the only drug currently marketed in the US for emergency contraception, has a number
of limitations for use in this indication. Like all previous synthetic hormones that have been evaluated
for use as post-coital contraceptives, the use of levonorgestrel for emergency contraception emerged
empirically. The levonorgestrel approval in the US was based primarily on results from two large-scale
WHO-sponsored trials (Ho et al, 1993) (Task Force on Postovulatory Methods of Fertility Regulation,
1998)) that had a number of limitations, in particular they were performed in non-US (mainly Chinese)
populations and without systematic pregnancy testing at follow-up. More importantly, the main

May 2010 Page 25 of 108
limitation of levonorgestrel lies in its rather short window of efficacy. The WHO-sponsored studies of
levonorgestrel consistently found that its efficacy decreased with time, reflected by the increasing
pregnancy rate for each additional 24-h interval elapsed between intercourse and treatment (Figure 4).
One of these trials (von Herzten et al, 2002) enrolled women up to 120h after intercourse, and the
failure rate almost doubled in women receiving emergency contraception 45 days vs. 13 days after
unprotected intercourse. Available evidence indicates that levonorgestrel has only limited effectiveness
beyond 72 h (Cheng et al, 2008), and levonorgestrel is not labeled for use beyond 72 h. The time-
dependent nature of levonorgestrel efficacy was a major argument in favor of the OTC switch, but
studies show that even in OTC settings a significant proportion of women continue to obtain
emergency contraception two or more days after intercourse (Marston et al, 2005), when
levonorgestrel efficacy has already begun to decline.
Figure 4 Pregnancy rate of levonorgestrel EC Figure 5 Inhibition of follicular rupture for at least 5 days
according to time elapsed between unprotected after treatment with 0.75-mg levonorgestrel twice, 12h apart,
intercourse and treatment or placebo (Source: Croxatto et al. 2004)
(Source: von Hertzen et al. 1998)
2.70%
80%
60%
40% LNG
1.20%
Placebo
20%
0.40%
0%
<24 h 25 -48 h 49-72 h 12-14 mm 15-17 mm 18 mm
A plausible explanation for the time-dependent efficacy of levonorgestrel may be found in studies of
its mechanism of action for emergency contraception. Whereas levonorgestrel is able to block or delay
ovulation when administered early in the follicular phase (when the leading follicle is 12-14 mm in
size), once the leading follicle has grown to 18 mm and LH levels have begun to rise, levonorgestrel
no longer interferes with the ovulatory process (Figure 5). This immediate pre-ovulatory phase of the
cycle is when both the probability of conception (Figure 6) and the frequency of intercourse (Figure 7)
peak, making it the most critical time in the cycle for a post-coital contraceptive to be effective.

May 2010 Page 26 of 108
Figure 6 Probability of conception according to cycle day Figure 7 Frequency of intercourse relative to
relative to ovulation (=0): the fertile window ovulation (the fertile window in grey)
(Source: Trussell et al. 1998) (Source: Wilcox et al. 2004)
0.40
0.30
0.20
0.10
0.00
Day - Day - Day - Day - Day - Day Day

5 4 3 2 1 0 1
A compound that is consistently able to prevent or delay ovulation when administered during the
immediate pre-ovulatory phase would be a highly effective method of emergency contraception. A
new generation of emergency contraception that works more consistently and over a longer period of
time than levonorgestrel offers expanded opportunities for women to prevent pregnancy after
unprotected intercourse.
When prescribed, such a method could provide a new opportunity for physicians to counsel their
patients and could serve as a springboard for discussions on pregnancy risk, errors of contraceptive use
and the risks of temporary discontinuation of contraception. By providing ongoing support for
effective use of contraception, healthcare professionals have a key role in anticipating womens need
for contraceptive backup and make it easier for their patients to access a safe, convenient and very
effective emergency contraceptive, offering them a better chance of avoiding to become pregnant in
case of unprotected intercourse. Ultimately, this method could give women a better chance of avoiding
an unintended pregnancy.

May 2010 Page 27 of 108
4 ULIPRISTAL ACETATE PRODUCT RATIONALE
4.1 Key points
Ulipristal acetate is a synthetic steroid derived from 19-norprogesterone that binds the progesterone
receptor with high affinity (progesterone receptor modulator).
Ulipristal acetate was evaluated for safety and efficacy in a battery of nonclinical and clinical
studies designed with input from the FDA, sponsored in turn by NICHD, then HRA Pharma.
The pharmacological rationale for its efficacy as an emergency contraceptive was established in
proof-of-concept models of peri-ovulatory and/or post-coital administration in animals that
consistently showed dose-dependent inhibition of ovulation and prevention of pregnancy.
Repeated administration of high doses to pregnant animals interrupted gestation; a battery of

reproductive toxicity studies in animals revealed no indications of teratogenic effects and no
adverse effects on the development or fertility of the F1 generation.
A series of clinical pharmacodynamics studies with mid-follicular, pre-ovulatory, early luteal and
mid-luteal dosing in healthy cycling women demonstrated significant delay in follicular rupture
following pre-ovulatory treatment, even in women in whom LH levels had begun to rise, thereby
confirming the promise of the compound for use as a post-coital contraceptive.
4.2 Product background
Progesterone plays a pivotal role in reproduction in many species. It is involved in the control of
ovulation, implantation, and maintenance of pregnancy, and withdrawal of progesterone at the end of a
nonfertile cycle results in menstruation in humans and nonhuman primates (Amoroso et al, 1962), Reel
et al, 1979), (Csapo et al, 1978). In the uterus, progesterone controls the growth and differentiation of
endometrial and myometrial cells and directly regulates a variety of cell functions; it also acts
indirectly by functionally opposing various estrogen effects. In the nonpregnant uterus, progesterone
exerts both inhibitory and stimulatory effects on cell proliferation in a cell- and tissue-specific manner.
Progesterone triggers the physiological mechanisms leading to ovulation, with the preovulatory rise of
progesterone levels having been shown to be a prerequisite for the rise of gonatropins; inhibition of
this preovulatory progesterone rise constitutes an interesting target for contraception (Zalanyi, 2001).
Progesterone mediates its physiological effects through interaction with the progesterone receptor, a
member of the superfamily of nuclear receptors. The recognition of the important role of progesterone
in reproduction led to the development of synthetic progesterone receptor ligands, also known as
selective progesterone receptor modulators (SPRMs). The synthesis of mifepristone, the first
progesterone and glucocorticoid receptor antagonist, was a starting point of drug discovery for
progesterone receptor modulators throughout the world, with much attention focused on finding
compounds with increased progesterone antagonistic potency and reduced antiglucocorticoid activity

May 2010 Page 28 of 108
compared with mifepristone (Teutsch et al, 1994), (Spitz et al, 1993). Ulipristal acetate, which binds
strongly to the progesterone receptor and stabilizes it in an antagonist conformation (Figure 8), is a
result of this search.
Figure 8 Overlay of progesterone receptor ligand binding domain with ulipristal acetate (yellow) or progesterone
(turquoise)
Also known as CDB-2914, HRP-2000 and RTI-3021-012, ulipristal acetate was originally synthesized
by Research Triangle Institute (RTI) under contract with the National Institute of Child Health and
Human Development (NICHD) (Cook et al, 1992 and 1994). Considering its ability to modulate the
progesterone receptor with reduced anti-glucocorticoid activity relative to other SPRMs, NICHD
sought to develop the compound for therapeutic and contraceptive uses, in particular as an emergency
contraceptive drug for postcoital use (Wagner et al, 1996). In support of the development of ulipristal
acetate as an emergency contraceptive agent, the Contraceptive Development Branch (CDB) of
NICHD carried out pharmacology and toxicology studies on the compound, synthesized bulk
quantities of the drug, applied for and obtained an IND in 1995, and proceeded to conduct Phase 1 and
Phase 2/3 clinical studies (Rao et al, 1999 and 2000).
HRA Pharma, a European pharmaceutical company that has been involved in the field of EC for more
than a decade, licensed-in ulipristal acetate in 2000 in view of registration and marketing as a next-
generation emergency contraceptive. HRA Pharma entered into a Collaborative Research and
Development Agreement with NICHD in 2002, and development of the compound was thereafter
undertaken in a collaborative fashion, with HRA Pharma taking over sponsorship of all subsequent
manufacturing, nonclinical and clinical trials for EC (Figure 9). In addition, HRA Pharma has initiated
development programs in other reproductive health indications, either alone or in partnership with
other organizations, which are currently ongoing.

May 2010 Page 29 of 108
4.3 Overview of development program
4.3.1 Nonclinical studies
The nonclinical program conducted by NICHD served to establish the primary pharmacodynamic
properties of ulipristal acetate as well as provide toxicology data from single and repeated-dose studies
(up to 6 months in rat and monkey), genotoxicity and aspects of reproductive toxicity.
HRA Pharma undertook an additional program of safety pharmacology studies as recommended in

ICH guidelines S7 and S7B. Pharmacokinetic studies were established to develop and validate a
specific bioanalytical assay capable of determining levels of plasma levels of ulipristal acetate and its
principal circulating metabolite, CDB-3877. Radiolabelled (14C) ulipristal acetate was also
synthesized and pharmacokinetic studies conducted in rat and monkey to investigate the absorption,
distribution and excretion of radiolabelled material as well as investigation of metabolism.
A program of GLP-compliant studies was undertaken in order to address the potential of in vivo drug-
drug interactions of ulipristal acetate and CDB-3877, in particular inhibitory or induction effects on
cytochrome P450 enzyme activities. Finally, to address concerns over the potential consequences of
off-label use of ulipristal acetate relatively late in pregnancy, a peri-and post-natal toxicity study was
conducted in rats, with ulipristal acetate being administered from day six of gestation through to
weaning.
The overall nonclinical data package, as reviewed with the FDA at the December 2008 pre-NDA
meeting, was considered adequate to support the application for use of ulipristal acetate as an
emergency contraceptive with a single oral dose of 30mg. Because ulipristal acetate is proposed for
use only in women, the nonclinical program of studies was conducted primarily in female animals.
4.3.2 Clinical studies
The initial clinical pharmacodynamics program sponsored by NICHD included a series of three
pharmacodynamic studies in healthy women volunteers designed to examine the effects of single doses
of ulipristal acetate when administered at different points in the menstrual cycle: mid-luteal phase
administration (LH+6/8), mid-follicular (follicle size 14-16mm) and early-luteal phase administration
(LH+2).
Based on pharmacological and pharmacodynamic profile of the compound as demonstrated in the

Phase 1 studies, and the results of the dose-ranging pharmacodynamic trials, NICHD initiated studies
of a 50-mg dose of the compound as an emergency post-coital contraceptive, in other words, as a
treatment aimed at preventing pregnancy after unprotected sexual intercourse.
The safety, efficacy and tolerability of ulipristal acetate for EC up to 72 h after unprotected intercourse
were evaluated in two double-blind Phase 2/3 studies. The first study compared a single 50-mg dose of
ulipristal acetate with FDA-approved levonorgestrel (two 0.75-mg doses taken 12 h apart), and

May 2010 Page 30 of 108
following conclusive results of the first one a second study was initiated to compare 50-mg with a
lower, 10-mg dose. Both studies indicated that a single dose of 50-mg ulipristal acetate appeared safe
and effective for EC.
These efficacy trials were ongoing when HRA Pharma licensed-in the compound. In parallel to
conducting complementary nonclinical trials, HRA Pharma proceeded to scale up the drug
manufacturing process and re-developed the pharmaceutical formulation via micronization and
formulation into a tablet in preparation for commercial manufacture (NICHD trials had been
conducted with crystalline active substance in gelatin capsules). HRA Pharma subsequently conducted
a repeated-dose pharmacodynamics trial with 12-weeks of daily dosing in healthy women volunteers.
In an effort to inform dose selection for the pivotal HRA Pharma EC trials, a pharmacokinetic bridging
study of three different drug formulations at the same dose was undertaken. Based on results of this
study and on an indirect pharmacokinetic comparison with data on the absorption of the 50-mg
NICHD capsule, a 30-mg tablet was chosen for evaluation in pivotal efficacy trials. The absorption
profile of this formulation was subsequently confirmed in multiple pharmacokinetic trials, and its
effects on follicular rupture when taken immediately prior to ovulation were evaluated.
The pivotal clinical efficacy program consists of two large-scale efficacy trials Studies 509 and 513,
designed to demonstrate the safety and efficacy of ulipristal acetate for EC up to 120 h after
unprotected intercourse. The study designs and analysis plans underwent prior FDA review via SPA
(Section 4.4), and the methods and results of these studies are described in detail in Section 4.8. Both
studies met their primary endpoints and were statistically conclusive.
A summary of all thirteen clinical studies is presented in Appendix 1.
4.4 Regulatory history
4.4.1 Interactions with FDA
The development program was conducted in close coordination with FDA and under FDA guidance.
Ulipristal acetate was developed under one investigational new drug application (IND 49,381) which
was opened by NICHD in 1995 and transferred to HRA Pharma effective January 2006. All efficacy
studies were conducted under IND. A summary of key interactions with FDA is provided in Figure 9.
HRA Pharma submitted the current NDA on October 15, 2009.

May 2010 Page 31 of 108
Figure 9 Key interactions with FDA
Endof Pre Endof

FDA Phase Phase Phase
meetings 1 2/3 2/3 SPA PreNDA
1990 1995 2000 2005 2010

Preclinical
Formulation
development
PK/PD
Efficacy/
Safety
NICHD sponsored trials HRAPharmasponsored trials
As early as 1996, FDA reviewed the available toxicology and Phase 1 trial results and provided
guidance on the preclinical studies to be carried out and the design requirements of necessary Phase
2/3 efficacy trials. The proposed Phase 2/3 protocol and clinical development program were discussed
again in 1998.
In April 2004, FDA reviewed the results of the Phase 2/3 efficacy trials and provided guidance was
given regarding the proposed further clinical program: the Agency highlighted that two adequate and
well-controlled studies are generally required for a new molecular entity and stated that a comparative
study against an approved emergency contraceptive drug would be preferred to an open-label study.
Although the FDA agreed that subjects could be enrolled up to 120 h after unprotected intercourse,
primary efficacy was to be based upon the 72-h timeframe because of the limitation in the approved
product.
FDA and HRA agreed via a Special Protocol Assessment (SPA) on the design of two pivotal Phase 3
trials in 2006. Key agreements with FDA are summarized in Table 4.

May 2010 Page 32 of 108
Table 4 Summary of key agreements on Phase 3 program with FDA from SPA
Topic Agreement
Primary efficacy analysis Comparison of the observed pregnancy rate to the expected pregnancy rate (calculated
using Trussells pooled recognizable set of conception probabilities)
Primary efficacy population Modified intent-to-treat (mITT) comprising all subjects:
- enrolled and randomized/treated
- participating for the first time in the study
- age 35 or less
- with a known pregnancy status at follow-up
- excluding pregnancies not incompatible with treatment failure because pre- or post-
treatment (assessed by independent DSMB)*
Other efficacy analysis Secondary efficacy analyses to be performed on:
populations - mITT2 population (excluding only confirmed pre-treatment pregnancies)
- ITT population (including all pregnancies, regardless of DSMB assessment)
Condition of study success Success if positive outcome for the primary efficacy analysis AND positive outcome for
inferiority to the clinical interest limit 4%
Non-inferiority versus LNG Secondary efficacy endpoint (Study 513)
Safety assessment Laboratory testing to on a subset of 100 women and all repeat users in Study 509
Eligibility criteria Enrollment of subjects >35 and provision for multiple enrollments
* FDA requested that CRFs for all pregnancies be submitted so as to re-assess the DSMBs assessment
During a pre-NDA meeting in December 2008, FDA requested direct bridging studies between the two
formulations in order to utilize efficacy and safety data from the NICHD efficacy trials, but since the
NICHD formulation was no longer available, HRA Pharma described the indirect comparison that
would be presented to allow some reliance on safety data obtained in Phase 2. FDA acknowledged
HRA Pharmas plan to conduct a secondary analysis including all pregnancies as well as only on-
treatment pregnancies but specified the Agency may consider this the appropriate primary analysis
population.
4.4.2 Foreign approvals
HRA Pharma submitted an application for European marketing authorization for ulipristal acetate on
May 30, 2008 via the centralized procedure. Following review by the European Medicines Agency, the
product was approved for marketing by the European Commission on May 15, 2009 under the brand
name ellaOne. The approved indication is EC within 120 hours (5 days) of unprotected sexual
intercourse or contraceptive failure. ellaOne was launched in October 2009 and is currently marketed
in 21 EU countries.
4.5 Preclinical overview
4.5.1 Primary Pharmacology
Ulipristal acetate shows high affinity for the progesterone and glucocorticoid receptors, much lower
affinity for the androgen receptor and essentially no affinity for the estrogen receptors.
With respect to the progesterone receptor, functional assays using cells expressing one or the other of
the two PR isoforms (PR-A or PR-B) were used to elucidate ulipristal acetate activity at the receptor.

May 2010 Page 33 of 108
Whereas progesterone activity was similar in cells expressing either isoform, ulipristal acetate exerted
progesterone-like agonist effects via the PR-B isoform on a subset of regulated genes while it
exhibited antagonistic properties via PR-A on a distinct subset of genes, indicating that ulipristal
acetate exerts both agonist and antagonist activities via the receptor isoforms in a gene-selective
manner (Study 459).
When comparing ulipristal acetate activity at the progesterone and glucocorticoid receptors, whereas
ulipristal acetate shows similar affinity for the two receptors, this similarity is not reflected in measures
of functional activity. In in vitro assays designed to evaluate its antagonistic activities, ulipristal acetate
acts as an antagonist at both the glucocorticoid and the progesterone receptors sites. However, it
displays a ten- to thirty-fold higher potency in antagonising the progesterone-receptor mediated R5020
stimulation of endogenous alkaline phosphatase or transcriptional activity in T47D-CO cells, than in
antagonising the glucocorticoid-receptor mediated dexamethasone stimulation of transcriptional
activity in HepG2 cells. Studies addressing the mechanism of action of ulipristal at glucocorticoid
target genes have shown that, ulipristal acetate functioned as a competitive antagonist at the
glucocorticoid receptor, since the resultant ligand receptor complex was unable to bind DNA.
Furthermore, in studies to examine the localization of the glucocorticoid receptor ligand complex in
COS-1 cells, ulipristal acetate did not promote efficient translocation of the glucocorticoid receptor to
the nucleus (Study 403).
In in vivo tests investigating hormonal antagonism or agonism, ulipristal acetate showed clear
antiprogestogenic activity but was devoid of estrogenic or androgenic activity whilst showing weak
anti-androgenic activity (Table 5).

May 2010 Page 34 of 108
Table 5 In vivo hormonal activity of ulipristal acetate (Study 404)
Activity Test system Results

Anti-progestogenic Anti McGinty test: Ligation of both uterine Ulipristal acetate was administered at 0.25,
horns in estradiol-primed immature rabbits. 0.5 and 1g per horn. At the highest dose
Test compound injected into one ligated UPA totally inhibited the progesterone-
horn and vehicle into other. Progesterone induced stimulation of endometrial glandular
was administered s.c. for 3 days before proliferation.
animals were euthanized and uteri examined
microscopically for the degree of
endometrial glandular proliferation.
Anti-Clauberg test: Estradiol administered Ulipristal acetate was administered p.o. at
for 6 days to immature rabbits before 5 daily doses of 0.2, 1 and 2 mg/day. Full inhibition
doses of progesterone and test compound;, of progesterone-induced stimulation of
animals euthanized and uteri examined endometrial glandular proliferation was
microscopically for the degree of observed at the highest dose level.
endometrial glandular proliferation
Antiuterotropic Immature rats dosed for three days with Ulipristal acetate (0.1 to 10 mg p.o., total
activity estradiol and test compound. Animals dose) showed modest antiuterotropic
euthanized 24 h after last dose, uteri excised, activity.
cleaned and weighed.
Uterotropic activity Immature rats dosed for three days with test Ulipristal acetate (1-mg total dose) did not
compound. Animals euthanized 24 h after show uterotropic activity
last dose, uteri excised, cleaned and
weighed.
Androgenic activity Orchidectomised immature rats were given Ulipristal acetate (20 or 40 mg, total dose)
test compound for 7 days. Animals did not show androgenic activity.
euthanized 24 h after last dose, ventral
prostate and seminal vesicles excised,
cleaned and weighed
Anti-androgenic Protocol as above, except that 2.4mg/day of Ulipristal acetate (10, 20, 40 mg p.o., total
activity testosterone was administered at the same dose) showed modest activity with ~40%
time as test compound inhibition at 40mg
Inhibition of ovulation by ulipristal acetate has been investigated in rodents. In rats, ulipristal acetate
was shown to prevent ovulation when administered on the day of proestrus immediately prior to the
surge in gonadotrophins, with activity seen after single oral doses of 0.5 mg/rat and higher (Table 6;
Study 405).
Table 6 Inhibition of ovulation by a single oral dose of ulipristal acetate administered to rats on the day of proestrus
(Study 405)
Treatment group
Ovulated/treated
(mg/rat)
Vehicle 16/16
0.5 5/8*
1 3/8*
2 0/8*
* p<0.05 vs. vehicle
Ovulation was also prevented in a super-ovulation model in gonadotrophin-primed mice; 20 or

40 mg/kg of ulipristal acetate administered 1 h before injection of human chorionic gonadotropin

May 2010 Page 35 of 108
inhibited ovulation (Palinisamy et al, 2006). This effect was proposed to result from a direct effect of
ulipristal acetate on the ovary, interfering with endothelin signalling pathways.
The post-coital activity of ulipristal acetate was investigated in rats and rabbits using a number of
dosing regimens. In these species, coitus either induces the gonadotropin surge immediately thereafter
(rabbit) or only takes place once the ovulatory stimulus has occurred (rat). At a single oral dose of
2 mg/day in rats, ulipristal acetate completely inhibited gestation when given on day 4 after mating
only (Study 405), (Table 7). This effect was blocked by coadministration of progesterone (Study 406).
High doses of ulipristal acetate were also effective in inhibiting gestation when daily administered on
days 0-3 after mating in rats and rabbits (Studies 405 and 406), (Table 7).
Table 7 Post-coital activity of ulipristal acetate in rats and rabbits
Dosing regimen Treatment Pregnant animals Normal concepti Resorbing concepti

(mean + SE)
Rat : Single dose
Day 0 Vehicle 9/10 14 + 1 0.2 + 0.1
Day 0 9/10 13 +1 0.1 + 0.1
Day 1 p.c. 1 9/10 12 +1 0.4 + 0.2
Day 2 p.c. 9/10 12 +1 0.8 + 0.4
2mg
Day 3 p.c. 10/10 12 +1 0.5 + 0.3
Day 4 p.c. 0/10* - -
Day 5 p.c. 2/10* 5 7.0
Rat : Repeated doses
Vehicle 9/10 14 + 2 0.8 + 0.2
1mg/day 3/10* 5+5 3.3 + 1.8
Day 0 - Day 3 p.c.
2mg/day 0/10* - -
4mg/day 0/10* - -
Rabbit : Repeated doses
Vehicle 4/4 9+2 0.8 + 0.8
2mg/day 5/5 8+1 0
Day 0 Day 3 p.c. 4mg/day 4/6 6+2 1.3 + 1.5
8mg/day 2/6 4 0
16mg/day 0/6* - -
1
: p.c. = post coitum
* p<0.05 vs. vehicle
Repeated high doses of ulipristal acetate (30 mg/animal) given later in established gestation to guinea-
pigs (Days 43-44) interrupted gestation in 6/8 animals (Study 407). The NOEL in this model was 3
mg/animal. The activity of repeated doses of ulipristal acetate was also investigated on early gestation
in monkeys. At a dose level of 5 mg/kg administered from Day 23 to Day 26 of gestation, ulipristal
acetate terminated gestation in 2/5 animals, whilst the NOEL was 0.5 mg/kg. In addition, pups born to
monkeys in which gestation was not interrupted developed normally.

May 2010 Page 36 of 108
4.5.2 Safety pharmacology
A battery of safety pharmacology studies was conducted in accordance with ICH guidelines, supported
by pharmacokinetic studies at the same dose levels (5, 25 and 125 mg/kg) showing that the top dose of
125mg/kg in these studies give Cmax values for ulipristal acetate of 8908 and 7360 ng/mL in rats and
dogs, respectively, which are respectively 50 and 42 times the Cmax in women after an oral dose of 30
mg.
The results are summarized in Table 8.
Table 8 Safety pharmacology profile of ulipristal acetate
Test system Results

Irwin test in rats: 5, 25 125 mg/kg p.o., observation for up No significant behavioural or physiological changes
to 24 h post-dose observed
Respiration rats and tidal volume in conscious rats: 5, 25 No relevant effect on respiration rate or tidal volume
125 mg/kg p.o., observation for up to 4 h post-dose
Action potentials in isolated dog Purkinje fibres: 1, 3, 10 No effect on resting membrane potential, maximum rate of
M (0.475-4.75 g/mL) in vitro with stimulation of fibres depolarisation or action potential duration
0.5, 1and 3 Hz
Effect on HERG tail current in transfected HEK293 cells: Ulipristal acetate had no effect on HERG tail current
10 M (4.75g/mL)
Cardiovascular effect in conscious telemetred dogs: 5, 25 25 and 125 mg/kg of UPA increased blood pressure for up
125 mg/kg p.o., observation for up to 24 h post-dose to 6 and 24 h post-dose, respectively. There were no
effects on heart rate or on any aspect of ECG (RR, PR,
QT, QTc intervals or QRS duration)
4.5.3 Pharmacokinetics
Pharmacokinetic studies identified the principal metabolites of ulipristal acetate to be the mono- and
di-N-demethylated derivatives, CDB-3877 and CDB-3963 (Studies 425, 426, 429). Pharmacological
studies showed CDB-3877 to have similar affinity to ulipristal acetate for the progesterone receptor
with CDB-3963 less potent; functional in vitro and in vivo antiglucocorticoid activity was even less
than that of ulipristal acetate (Studies 449, 450).
Ulipristal acetate was rapidly and completely absorbed after oral dosing (Studies 425, 426). It is highly
bound to plasma proteins (96.7-99.5%) across a range of species (Study 428). Tissue distribution of
radioactivity was widespread and a study in pigmented rats showed selective binding in pigmented
tissues as compared to albino animals (Study 425). Excretion of radioactivity was predominantly
faecal in both rats and monkeys with bile shown to play a major role in rats (Studies 425, 426).
In vitro metabolism studies with human liver microsomes in the absence and presence of NADPH
(Study 429) implicated cytochrome P450 (CYP) enzymes in the metabolism of ulipristal acetate and
studies with Supersomes showed CYP 3A4 to be the major isoenzyme involved (Study 430). Using
human liver microsomes, ulipristal acetate was shown to inhibit CYP2C9, CYP2D6 and CYP3A4
activities, but only weakly, showing approximately 50% inhibition of these isoenzymes at the high

May 2010 Page 37 of 108
concentration of 100 M (47.5 g/mL) (Study 476). In human hepatocytes, ulipristal acetate at
concentrations up to 5 M did not demonstrate any ability to induce CYP1A2 and CYP3A4 (Study
477).
4.5.4 Toxicology
The repeated-dose and reproductive toxicology studies conducted with ulipristal acetate are listed in
Table 9.
Table 9 Repeated-dose and reproductive toxicology studies with ulipristal acetate
Study type Duration of dosing Dose levels (mg/kg/day)

Repeated-dose toxicity
Rat subacute 14 days 0, 4, 20, 100
Rat chronic toxicity 6 months 0, 1, 5, 25
Monkey subacute 14 days 0, 20, 100
Monkey chronic toxicity 6 months 0, 1, 5, 25
Reproductive toxicity
Male rat fertility 14, 35 or 70 days premating 0, 10
Pilot rat embryofoetal GD6-GD15 0, 0.1, 0.3, 1.0, 3.0, 10.0
Rat embryofoetal GD6-GD17 0, 0.1. 0.3, 1.0
Rabbit embryofoetal GD6-GD18 0, 0.1, 0.3, 1.0
Rat pup development GD0-GD3 0, 0.5, 1 mg/rat
Rat parturition GD17-GD19 0, 2, 4, 8 mg/rat
Pilot rat peri/post natal development GD6-LD6 0, 0.1, 0.3, 1
Rat peri/post natal development GD6-LD20 0, 0.03, 0.1, 0.3
The toxicological profile of ulipristal acetate emerging from the repeated-dose toxicity studies is a
consequence of its pharmacological activity as a progesterone and glucocorticoid antagonist with
disruption of the hypothalamic-pituitary-adrenal axis and reproductive systems.
Organ weight analysis in the 6-month study in the rat showed increased liver and adrenal weights and
decreased ovaries, uterus and thyroid weights at the 5 and 25 mg/kg/day dose levels. On histological
examination, these correlated with adrenal cortical and liver hepatocyte hypertrophy, ovarian follicular
cysts and follicular atresia and uterine glandular dilation; pituitary hyperplasia and mammary
galactoceles were also noted. These histological changes were most notable in animals treated with 5
or 25 mg/kg/day but the changes in mammary glands and ovaries were also seen at 1 mg/kg/day.
Serum corticosterone and prolactin levels measured at end-treatment were increased. Treatment-
related changes were seen at all dose levels and it was not possible to determine a NOEL (Study 435).
The 6-month study in monkeys also showed disruption of the hypothalamic-pituitary-adrenal axis with
increased levels of cortisol and prolactin. Although hormone levels were altered at all dose levels, the
consequences appeared to be restricted to the 5 and 25 mg/kg/day dose levels. The menstrual cycle

May 2010 Page 38 of 108
was disrupted in mid- and high-dose animals with some high-dose animals being acyclic throughout
the study. Adrenal weights were increased in high-dose animals, consistent with the hypertrophy
observed at histology; although thymus weights were decreased at this dose level, there were no
histological correlates. Histology also showed cystic dilatation of uterine endometrial glands in mid-
and high-dose animals, consistent with unopposed estrogen stimulation, with one high-dose animal
showing mild squamous metaplasia. Serum levels of ulipristal acetate and immunoreactive metabolites
were monitored by RIA at intervals throughout the study at 4 h after dosing; these increased slightly
over the first 3 days of dosing but were relatively stable thereafter with mean values varying over the
ranges 60.4-106.9, 380.7-864.3 and 1836.8-4171.7 ng/mL in the 1, 5 and 25 mg/kg/day groups,
respectively (Study 436).
Reproductive toxicity studies were limited in dose by the progesterone antagonist effects of ulipristal
acetate in preventing the maintenance of gestation. In both rats and rabbits, the maximum dose in the
formal embryofoetal development studies was limited to 1 mg/kg/day, but interruptions of gestation
were observed even at this level. However, no indications of any teratogenic effect were observed in
either species (Studies 444, 445).
Two rat studies investigated effects of exposure of pregnant females on eventual pup development. In
the first study, rats received 0.5 and 1 mg/rat/day during days 0-3 after mating. The number of
pregnant animals was reduced at the high-dose level and gestational length was increased at both dose
levels. The development of F1 generation pups was followed up to and including their reproductive
capacity and no adverse effects were observed. The NOEL for pup development was evaluated at
1 mg/rat/day (Study 446), (Table 10).

May 2010 Page 39 of 108
Table 10 Reproductive and developmental toxicity of ulipristal acetate given

during day 0 to day 3 of gestation in the rat
Parameter Control 0.5 mg/rat/day 1.0 mg/rat/day

F0 data:
- Body weight day 20 (g) 431.15.8 427.37.7 340.917.4*
- Gestational length (days) 21.50.2 22.30.2* 22.70.7
F0 reproductive data:
- Number of pregnant females (%) 100 100 30*
- Parturition incidence (%) 100 100 100
- Live litter size (day 0) 13.40.7 14.00.8 7.74.7*
- % Live birth 94.52.2 93.30.7 100
- % Survival (day 1) 99.40.6 99.30.7 100
F1 male fertility data:
- Fertility (%) 100 97.4 100
- % Female partners pregnant 93.8 88.5 94.4
- Normal implants 14.90.3 14.40.4 15.10.8
- Abnormal implants 1.90.2 1.80.3 2.10.7
F1 female fertility data :
- Fertility (%) 82.5 82.1 80
- Normal implants 16.30.5 16.90.6 17.32.1
- Abnormal implants 1.60.2 2.30.5 1.70.3
* p<0.05 vs. control
In the second study, ulipristal acetate was administered at the doses of 0.03, 0.1 and 0.3 mg/kg/day
from day 6 of gestation through to weaning of the F1 offspring. The development of F1 generation pups
was followed up to and including their reproductive capacity. The dose of 0.3 mg/kg/day was defined
as the maximal tolerated dose, but was still associated with increased perinatal death of the offspring
(Study 471). Nevertheless, all the pups that survived at this dose level developed normally. Results
presented on Table 11 show that no adverse effects were observed after exposure of pregnant female
during gestation to ulipristal acetate, on the development and reproductive capacity of the F1
generation. The NOEL for F0 generation and pup development was 0.01 mg/kg.

May 2010 Page 40 of 108
Table 11 Reproductive and developmental toxicity of ulipristal acetate given

from day 6 of gestation through to weaning in the rat
Parameter Control 0.03 mg/kg 0.1 mg/kg 0.3 mg/kg

F0 Females Reproductive data
Number evaluated 25 24 23 22
Number of pregnant rats (%) 100 100 92 92
Gestational length (days) 21. 22.0 21.7 21.5**
Females with stillborn pups (%) 0 12.5 4.3 13.6
Mean Pre-birth loss (%) 7.6 7.8 7.0 27.2***
Viability index at day 4 (%) 99.4 99.0 100.0 94.4
Viability index at day 21 (%) 99.0 100.0 98.9 100.0
F1 Females (Postweaning)
Number evaluated 25 25 25 25
Number of pregnant rats (%) 100 96 88 96
Mean No. Corpora Lutea 17 17 18 18
Mean No. Implantations 17 16 16 16
Mean % Preimplantation Loss 5.0 6.3 8.4 9.2
F1 Litters
N of litters evaluated 25 24 22 23
Mean No. Live Conceptuses/Litter 16 15 16 15
Mean % Postimplantation Loss 3.9 5.5 3.4 4.6
** p<0.01 vs. control
*** p<0.001 vs. control
Thus, in studies at doses of ulipristal acetate which allowed gestation to be maintained, there were no
indications of a teratogenic effect and no adverse effect on the development of the F1 generation.
Moreover, as discussed above, no adverse effect on F1 animals was observed in monkeys in which
gestation was maintained after receiving 0.5 or 5 mg/kg/day on days 23-26 of gestation.
Ulipristal acetate did not show any evidence of genotoxic potential in a range of regulatory
genotoxicity tests.
4.6 Clinical Pharmacology & Mechanism of Action
The effects of single doses of ulipristal acetate on ovarian function and cycle parameters were
evaluated in four pharmacodynamic studies in healthy female volunteers.
In an initial series of three studies sponsored by NICHD, single doses ranging from 10 to 200 mg were
administered at different phases in the menstrual cycle (mid-luteal, mid-follicular or early luteal
phase).
In the first study (503) (Passaro et al, 2003), ulipristal acetate or placebo was administered to 36
women at the mid-luteal phase of the menstrual cycle. No significant effects on menstrual cycle length
were observed at doses of 0 to 100 mg. However, all six women in the 200-mg dose group had a

May 2010 Page 41 of 108
shortened luteal phase and early menses. In addition, prolactin, renin, ACTH, cortisol and thyroxin
were assayed, and the results showed no apparent effect of ulipristal acetate treatment on the
hypothalamic-pituitary- adrenal axis or other endocrine function. There were no statistically-
significant changes in urinary free cortisol, plasma renin activity, plasma prolactin or thyroxin levels
following ulipristal acetate administration, as compared with baseline. The diurnal variation of cortisol
(8:00 am: 330 20 nmol/l vs. 8:00 pm: 85 8 nmol/l, p<0.001) remained intact during the 24 h
immediately following ulipristal acetate administration.
In the second study (505) (Stratton et al, 2000), 44 women were given either placebo or ulipristal
acetate (10, 50 or 100 mg) during the mid-follicular phase when they had a dominant follicle that was
14 to 16 mm by ultrasound examination. The results of this study indicate that ulipristal acetate
suppressed growth of the lead follicle. In the majority of cases, the follicles resumed growth after four
days, but in some subjects the lead follicle stopped growing and a new follicle began to grow (one at
10 mg, three at 50 mg, and four at 100 mg). All subjects reported a delayed LH surge. A dose-
dependent reduction in plasma estradiol levels was observed during the first four days after dose. For
the 50- and 100-mg treatment groups, cycle length increased by approximately four days compared to
placebo. This overall increase was mainly secondary to the change in lead follicle observed in some
women. Compared with placebo, there was a significant delay in endometrial maturation 5-7 days after
actual ovulation in all ulipristal acetate arms in 70% of biopsy specimens. However, recent studies
suggest that endometrial dating does not correlate well with fertility (Coutifaris C et al, 2004). The
delay in follicular collapse induced by ulipristal acetate with escalating doses is summarized in Table
12.
Table 12 Effect of ulipristal acetate administered (when lead follicle is 14-16 mm)
on time to follicular collapse (Study 505)
Days from dose to follicular collapse

Dose
Mean (range)
Placebo (n=12) 5.8 (3-10)
UPA 10-mg (n=11) 6.8 (4-16)
UPA 50-mg (n=11) 10.3 (7-18)
UPA 100-mg (n=10) 12.7 (8-17)
In the third study (506) (Stratton et al, 2010), 56 women were administered either placebo or ulipristal
acetate (10, 50 or 100 mg) in the early luteal phase (within two days after LH surge). There was no
significant difference among the treatment groups in baseline, treatment or post-treatment menstrual
cycle length. Mid-luteal phase estradiol and progesterone levels 4-6 days after treatment were also
similar among groups. There was no significant delay in endometrial maturation in the 50- and 100-mg
groups compared to the placebo and the 10-mg group upon biopsy four to six days after ovulation.
Endometrial thickness on the day of treatment was similar in all women but was significantly
diminished at all doses on the day of biopsy. Early luteal administration increased glandular
progesterone receptor expression at the higher doses tested (50 and 100 mg) without affecting stromal
expression of the receptor, luteolysis or luteal phase length.

May 2010 Page 42 of 108
In a more recent study (511) (Brache et al, in press), 35 women were administered placebo or 30 mg
ulipristal acetate (to-be-marketed dosage form) in alternate cycles in a cross-over design when the
leading follicle reached 18 mm, at the presumed time of the LH surge when follicular rupture and
ovulation are imminent. Treatment effect on dominant follicle outcome 5 days after intake is reported
in Table 13; ulipristal acetate had a potent inhibitory effect on follicular rupture for more than five
days after treatment in a majority of cycles.
Table 13 Inhibition of follicular rupture with ulipristal acetate dosing when leading follicle is 18 mm (Study 511)
Subjects treated when leading Subset of subjects treated after onset of

Population follicle was 18mm LH surge
(N=34) (N=19)
Number of subjects (%) with follicle Placebo UPA 30-mg Placebo UPA 30-mg
rupture inhibition 5 days after dosing 0 (0.0%) 20 (58.8%) 0 (0.0%) 8 (42.1%)
p-value 0.0002 0.0047
Daily sampling was performed to determine the LH status of each woman at the time of dosing, and
the results showed that 19 subjects out of 34 were treated after LH levels had begun to rise (LH surge
onset). Inhibition of follicular rupture was highly dependent on LH status at the time of treatment
(Figure 10). Ulipristal acetate significantly inhibited follicular rupture even when given after the onset
of the LH surge.
Figure 10 Inhibition of follicular rupture at 5 days after treatment stratified by LH status at the time of treatment
(Study 511)
100 8/8
UPA 30 mg (n=34)
Placebo (n=34)
80
11/14
60
Percent (%)
40
20
1/12
0/12 0/6 0/16
0
Tx before LH surge onset Tx aftet LH surge onset but before Tx after LH peak
LH peak
The mean time elapsed from treatment intake to follicle rupture was significantly longer in ulipristal
acetate cycles (6.03 3.86 versus 2.41 1.31 days in placebo cycles, p < 0.0001). When treatment
was given after the onset of the LH surge, the mean time elapsed from treatment intake to follicle

May 2010 Page 43 of 108
rupture was still significantly longer in ulipristal acetate cycles (4.25 3.53 days) than in placebo
cycles (1.79 0.92 days) (p= 0.0507).
Mean LH levels after treatment intake are displayed in Figure 11. An immediate drop in LH levels was
observed on the day following ulipristal acetate intake if LH had not reached its peak level at the time
of treatment. Progesterone levels >10 nmol/L were observed in all cycles, despite delayed follicular
rupture. The mean highest progesterone level during ulipristal cycles was 49.2 18.3 and 53.5 16.0
for placebo cycles. However, progesterone rise was significantly delayed after ulipristal acetate
treatment following the delayed follicular rupture. Luteal phase parameters (duration, progesterone
level) were similar in ulipristal acetate and placebo cycles.
In addition, in this study, TSH was measured at screening and at the end of the study, and the results
showed no effect of ulipristal acetate treatment on TSH levels.
Figure 11 LH levels after dosing (Tx) either before the onset of the LH surge (left panel), after the onset of the LH
surge but before the LH peak (middle panel), or after the LH peak (right panel) (Study 511)
In summary, the pharmacodynamic data package provides evidence that a single dose of ulipristal
acetate, administered in the mid- or even late-follicular phase, significantly delays ovulation. The
longer ovulation can be delayed after intercourse, the lower the likelihood of fertilization. Late in the
follicular phase, once LH levels have begun to rise, levonorgestrel no longer inhibits follicular rupture.
This enhanced ability of ulipristal acetate to inhibit ovulation would suggest with biological
plausibility that ulipristal acetate should be a highly effective method of EC.

May 2010 Page 44 of 108
4.7 Rationale for dose determination
When HRA Pharma obtained the license for ulipristal acetate, the NICHD efficacy trials (Phase 2/3
Studies 507 and 508) were ongoing. The dose of 50 mg had been chosen based on pharmacodynamic
studies (Studies 503 and 505). The results of these efficacy trials, presented hereafter, informed the
development of the dosage form used in pivotal trials; they suggested that the 50-mg NICHD
formulation was equivalent or more effective than levonorgestrel and presented a lower pregnancy rate
compared to the 10-mg formulation. From a manufacturing perspective, commercialization of an
unmicronized formulation in gelatin capsules was not feasible because such a formulation is difficult
to reproduce in an industrial setting. Based on the results of a pharmacokinetic bridging study of three
different drug formulations (Study 501), micronization and tablet form significantly increased the rate
and extent of absorption, resulting in a relative bioavailability of 1.44. Taking into account that
ulipristal acetate absorption is linear for single doses in the range of 10 to 50 mg (Study 503), a 30-mg
dose of the micronized drug substance in tablet form was chosen to achieve an efficacy and safety
profile similar to that of the 50-mg gelatin capsule formulation. This 30-mg formulation was evaluated
in the pivotal Phase 3 registration trials.
4.8 Overview of efficacy trials
The efficacy, safety and tolerability of ulipristal acetate for EC have been evaluated in four clinical
trials: two performed by the NICHD (Studies 507 and 508, which are considered supportive for
registration because of their use of a developmental formulation) and two performed by HRA Pharma
(Studies 509 and 513, which are the pivotal registration trials). Three of the four trials have been
published (507: Creinin et al, 2006; 509: Fine et al, 2010; 513: Glasier et al, 2010).
In all four efficacy trials, women were eligible for enrollment if they presented to a participating
family planning center requesting EC within 5 days following unprotected intercourse or contraceptive
failure, if they had regular menstrual cycles and a negative high sensitivity urine pregnancy test.
Eligibility criteria were purposefully left as broad as possible to allow inclusion of a generalizable
study population, with lower age limits (16 or 18 years) applied according to local and national
regulations on age of majority for informed consent. Although primary efficacy analyses were
performed on women up to and including age 35, older women were eligible for enrollment.
Key elements of study design are presented in Table 14.
To determine the efficacy outcome (pregnancy or no pregnancy), systematic pregnancy testing was
performed at clinic follow-up, scheduled approximately one week after expected onset of next menses
after enrollment. The primary endpoint in the four efficacy trials was the pregnancy rate in the study
population, and the primary objective and main statistical methods of the Phase 2/3 studies are
summarized in Table 15 and of the Phase 3 pivotal studies are summarized in Table 16.

May 2010 Page 45 of 108
In each of the efficacy trials, an independent Data Safety Monitoring Board (DSMB) reviewed safety
data and incidence of pregnancy periodically. In the Phase 3 Studies 509 and 513, the DSMB also
assessed each pregnancy diagnosed using ultrasound, serum hCG and coital and cycle calendar data to
determine whether it was consistent with a treatment failure or a pre- or post-treatment pregnancy. The
DSMB performed the assessment without knowledge of treatment identity.
Table 14 Overview of design of efficacy studies
Study number 507 508 509 513

Sponsor NICHD NICHD HRA Pharma HRA Pharma
Phase 2/3 2/3 3 3
Design Randomized Randomized Open-label Randomized
Double blind Double blind Single blind
Time window Within 72 h of Within 72 h of 48 120 h after Within 120 h of
intercourse intercourse intercourse intercourse
Study sites 7 family planning 9 family planning 45 family planning 35 family planning
clinics (USA) clinics (USA) clinics (USA) clinics (24 USA, 10
UK, 1 Ireland)
Main eligibility Age 18 and more Age 18 and more Age 18 and more Age 16 (UK) / 18
criteria Regular cycle (24-42d) Regular cycle (24-42d) Regular cycle (24-35 d) (US/Ireland) and more
Not pregnant Not pregnant Not pregnant Regular cycle (24-35 d)
Not breastfeeding Not breastfeeding Not breastfeeding Not pregnant
No use of hormonal No use of hormonal No use of hormonal Not breastfeeding
contraception or IUD contraception or IUD contraception or IUD No use of hormonal
contraception or IUD
Treatments UPAum 50-mg UPAum 50-mg UPA 30-mg UPA 30-mg
+ placebo 12h later
UPA 10-mg LNG 1.5-mg
LNG 0.75-mg 2
12h apart UPAum 10-mg
(stopped prematurely)
Study schedule FU visit 5-7 days after expected onset of menses to verify pregnancy status by urine pregnancy testing
and return of menses. Additional visit 1 week later as needed to ascertain pregnancy status
Safety Adverse events & Adverse events & Adverse events, vaginal Adverse events &
reporting vaginal bleeding vaginal bleeding bleeding and lab vaginal bleeding
parameters (subset of
patients)
um: unmicronized formulation
4.8.1 Methods of efficacy trials
Studies 507 and 508 were performed in the US within the NICHD Contraceptive Clinical Trials
Network. As Study 508 was an extension of Study 507, their designs were nearly identical. The
statistical methods of these studies are described in Table 15.

May 2010 Page 46 of 108
Table 15 Statistical methods of NICHD supportive Phase 2/3 efficacy trials
507 508
Primary efficacy criterion Observed Pregnancy Rate (obs PR)
Sample size for primary N=1,540 (770 per group) N=744 (372 per group)
efficacy population
Primary efficacy population Treated, known pregnancy outcome* Treated, known pregnancy outcome, post-
treatment pregnancy
Primary question of interest Is the difference in PR between UPA 50- Is the difference in PR between UPA 10-mg
mg and LNG when taken within 72 h of and 50-mg when taken within 72 h of
unprotected intercourse smaller than the unprotected intercourse smaller than the
unacceptable margin of 2% in points? unacceptable margin of 2.5% in points?
Main statistical hypotheses** H0: UPA LNG + 0.02 H0: 10 50 + 0.025
H1: UPA < LNG + 0.02 H1: 10 < 50 + 0.025
Primary test Exact confidence interval of pUPA pLNG. Exact confidence interval of p10 p50.
H0 rejected if UL95%CI < 0.02 H0 rejected if UL95%CI < 0.025
Primary objective reached if Primary test is significant Primary test is significant
Rationale for the fixed limits 4% is half of the expected pregnancy rate 4% is half of the expected pregnancy rate in
(See secondary analyses for in the general unprotected population and the general unprotected population and is
Study 513) is the clinical interest limit for an EC. the clinical interest limit for an EC.
Expected rate for LNG or UPA = 2% Expected rate for UPA 50-mg = 1.5%
unacceptable margin = = 4% 2% = unacceptable margin = = 4% 1.5% =
2% 2.5%
Interim analysis for success No No
Main secondary efficacy Sub-populations analyses - Sub-populations analyses
analyses - Prevented fraction
*analysis performed first on population including all pregnancies; then repeated on efficacy evaluable population
excluding known pre-treatment pregnancies; the second approach is the same primary analysis population as Study 508
** H0: null hypothesis, H1: alternative hypothesis
The pivotal registration trials (Studies 509 and 513) using the to-be-marketed 30-mg dosage form were
designed to confirm the results of the NICHD efficacy trials using the final dosage form and to provide
evidence of the efficacy of ulipristal acetate for EC up to 120 h after unprotected intercourse, two days
longer than the approved time window for levonorgestrel. This Phase 3 pivotal clinical program was
reviewed with the FDA via the Special Protocol Assessment procedure (Section 4.4). Eligibility
criteria were purposely kept as broad as possible in order to favor generalizability of study results.
Interim analyses using the alpha spending function were planned in both protocols in order to allow the
studies to be stopped prior to full accrual in case of success.
The statistical methods of these studies are presented in Table 16. The primary efficacy analysis
population was the modified intent-to-treat (mITT population) which included all randomized/treated
women with a first participation, a known pregnancy outcome and age 35 years, and excluded
pregnancies incompatible with treatment failure because pre- or post-treatment (assessed by DSMB).
In addition to the mITT population used for primary efficacy analysis, the following populations were
defined:
- ITT: included all randomized/treated women including protocol allowed subsequent participations.
This population has been used for description of demographics and safety analyses.

May 2010 Page 47 of 108
- ITT completers: included all randomized/treated women with a first participation and a known
pregnancy outcome. This population has been analyzed for assessing the sensitivity of primary
efficacy results.
- mITT2: included all randomized/treated women with a first participation, a known pregnancy
outcome, age 35 years, and excluded confirmed pre-treatment pregnancies. In accordance with
FDA recommendations, this population has also been analyzed for assessing the sensitivity of
primary efficacy results.
Table 16 Statistical methods of HRA Pharma pivotal Phase 3 efficacy trials
509 513
Primary efficacy criterion Observed Pregnancy Rate (obs PR)
Sample size for primary N=1200 N=1654 (827 per group)
efficacy population
Primary efficacy population Modified ITT (mITT): Modified ITT (mITT):
Treated, first participation, known Randomized, treated, first participation,
pregnancy outcome, known pregnancy outcome,
age 35 or less, age 35 or less,
pregnancy assessed as compatible with pregnancy assessed as compatible with EC
EC treatment failure by DSMB treatment failure by DSMB
Primary question of interest Is PR of UPA 30-mg inferior to expected Is PR of UPA 30-mg inferior to expected
PR (in the absence of contraception) and PR (in the absence of contraception) and
inferior to the clinical interest limit of 4% inferior to clinical interest limit of 4% when
when taken 48 to 120 h of unprotected taken within 72 h of unprotected
intercourse? intercourse?
Main statistical hypotheses* H0: UPA E(PR) H0: UPA E(PR)
H1: UPA < E(PR) H1: UPA < E(PR)
Primary test Agresti Coull CI Agresti Coull CI
H0 rejected if UL95% CI of PR < E(PR) H0 rejected if UL95% CI of PR < E(PR)
Primary objective reached if The 2 following H0 are rejected: The 2 following H0 are rejected:
H0: UPA E(PR) H0: UPA E(PR)
H0: UPA 4% H0: UPA 4%
Rationale for the fixed limits Actual expected rate of pregnancy in Same rationale as 509 for the unacceptable
(See secondary analyses for absence of contraception [E(PR)] in the limit of the observed pregnancy rate.
Study 513) studied population is the unacceptable OR = 1.6 is the OR of a difference of 1% in
limit otherwise the drug could be as good PR if the true PR of LNG is 1.7%. A
as no contraception. difference of 1% between two EC drugs is
close to the clinical irrelevance threshold.
Interim analysis for success Yes (n=900 mITT) Yes (n=1,200 mITT)
Main secondary efficacy - Sub-populations analyses - Non-inferiority analysis based on the CI of
analyses -Prevented fraction OR estimated through logistic regression
- Trend over time in pregnancy rate (H0: true OR of pregnancy of UPA with
respect to LNG 1.6)
- Analysis on 0-120 h time window
- Sub-populations analyses
- Prevented fraction
- Trend over time in pregnancy rate
* H0: null hypothesis, H1: alternative hypothesis

May 2010 Page 48 of 108
4.8.2 Rationale for the choice of clinical thresholds
Several clinical thresholds were retained in the four trials. The first was the expected rate of
pregnancies in the study population, calculated using published conception probabilities based on each
subjects day of intercourse relative to her expected day of ovulation (Trussell et al, 1998). Because
the expected rate of pregnancies that reaches approximately 8% in the overall unprotected population
(von Hertzen et al, 1998) may be different in the studied population, the expected rate as calculated
through Trussells probabilities is considered as an unacceptable limit. In other words the upper bound
of the 95% confidence interval of the pregnancy rate in the studied population must be smaller than the
calculated expected rate to accept a minimal effect of the EC.
Another limit has been retained as a clinical interest limit (also referred to as the clinical irrelevance
threshold in study protocols). This has been set at 4% which is one-half of the expected rate of
fertilisation for the general unprotected population. The pregnancy rate observed in the studies must be
incompatible with this limit (significantly lower than 4%) to consider the effect as fully relevant. The
margin of 2 % and 2.5% used in non inferiority test of Phase 2/3 trials 507 and 508 may not be
considered as the limit of clinical relevance but have to be interpreted as a non-acceptable difference.
The limit of 1.6 in the odds ratio of the comparative Phase 3 study 513 derived from a non inferiority
margin of 1% in percentage point which had to be close to the threshold of clinical irrelevance:
applying the 1% difference to the observed pregnancy rate of levonorgestrel in Phase 2/3 trial
(Pregnancy rate = 1.7%) we obtained an OR = 1.6. A positive non-inferiority test using this limit may
be interpreted as (or close to) equivalent or more efficacious than the comparator.
4.8.3 Methods of pooled efficacy analysis
Two sets of pooled analyses were carried out for efficacy purposes (Table 17).
Table 17 Summary description of pooled efficacy analyses
Type Main Objectives Studies Pooled

mITT pooled Phase 3 -To assess efficacy of ulipristal acetate over time from unprotected 509 (mITT)
intercourse 513 (mITT)
-To assess the effects of intrinsic and extrinsic factors on pregnancy rates
Meta-analysis -To estimate the advantage of ulipristal acetate over levonorgestrel 507 (EE)
-To identify the prognostic factors that contribute the most to the 513 (mITT)
explanation of the pregnancy rate
Firstly, data from the two Phase 3 trials (Studies 509 and 513) were pooled to create a new analysis
population (called the mITT pooled Phase 3 population) which included the primary efficacy
population (mITT) from each study (n= 2,180). The purpose of the planned pooled analysis was
mainly to assess efficacy of ulipristal acetate over time from unprotected intercourse. The pooled
analysis also served to assess the effects of intrinsic and extrinsic factors on pregnancy rates. The age

May 2010 Page 49 of 108
factor was analyzed on a larger database called ITT completer pooled Phase 3 in order to include
women aged over 35.
A second pooled analysis was performed with the databases from the two randomized trials that had a
parallel levonorgestrel group (Studies 507 and 513). The purpose of the exploratory second meta-
analysis was to estimate the effect of ulipristal acetate compared to levonorgestrel on a large database,
to check the robustness of the estimates under various approaches (various models and subgroups), to
identify the prognostic factors that contribute the most to the explanation of the pregnancy rate and to
search for particular conditions favorable to the use of one product or the other. Prior to pooling, the
homogeneity of treatment groups regarding factors potentially influencing pregnancy rate (response of
interest) was assessed. Like the main analysis of Phase 3 trials, a logistic model was used to explain
the occurrence of pregnancy in the two groups. In addition to study effect (constrained factor) and
treatment effect (factor of interest), the following confounding factors were included in some models
to assess their influence and estimate the adjusted effect of the treatment: age of subject, BMI, time
from unprotected intercourse to treatment intake, conception probability defined according to
Trussells method (Trussell, 1998) using set of pooled recognizable conception probabilities, time
from unprotected intercourse to the most fertile day (day of ovulation - 1), existence of further
unprotected intercourse and pregnancy history. The magnitude of treatment effect was estimated from
the model by the odds ratio (OR) with 95% confidence interval. As response (pregnancy rates)
corresponds to rare events, the odds ratio can be interpreted as relative risk. Likelihood ratio tests were
used to test the treatment or the factor effect.

May 2010 Page 50 of 108
5 CLINICAL EFFICACY
5.1 Key points
Four clinical trials conducted predominantly in the US enrolled more than 6,000 women (including
over 4,000 in ulipristal acetate treatment arms) to evaluate the efficacy of ulipristal acetate for the
prevention of pregnancy following unprotected intercourse or a contraceptive failure. This program
included two pivotal registration trials conducted with the to-be-marketed 30-mg tablet under a
special protocol assessment (SPA) with the FDA (Studies 509 and 513).
The primary efficacy criterion for all these studies was the pregnancy rate observed after
emergency contraception usage.
Both pivotal studies were conclusive and ulipristal acetate significantly reduced the pregnancy rate
by an average of approximately 2/3 in comparison with the expected pregnancy rate in the absence
of any intervention for emergency contraception.
Women were eligible for enrollment up to 120 hours after intercourse, and the effectiveness of
ulipristal acetate in reducing the pregnancy rate was consistent throughout the entire 120-hour
enrollment window.
Two trials (Studies 507 and 513) included an active levonorgestrel comparator. The odds ratios
(and 95% confidence intervals) of pregnancy with ulipristal acetate compared to levonorgestrel for
the two studies were 0.50 (0.18-1.24) and 0.57 (0.29-1.09) respectively, and for the combined
studies was 0.55 (0.32-0.93).
5.2 Summary of results from supportive efficacy trials (Phase 2/3 studies)
5.2.1 Study 507
Study 507 enrolled and randomized 1,672 subjects within 72 h of unprotected intercourse (Figure 12).

May 2010 Page 51 of 108
Figure 12 Study 507: Disposition of subjects
The ulipristal acetate and levonorgestrel treatment groups were comparable at baseline in terms of
demography and baseline characteristics (see Table 44 in Appendix 2).
The efficacy analyses performed, in turn, including all pregnancies and excluding pre-treatment
pregnancies were positive (difference was significantly better than the unacceptable limit of 2%).
These efficacy results are presented in Table 18. The pregnancy rates for both ulipristal acetate and
levonorgestrel were significantly below the 4% clinical interest limit, meeting one of the requirements
for a positive study.
In conclusion, this prospective, double-blind study demonstrates that the difference between ulipristal
acetate and levonorgestrel excluded the unacceptable difference of 2% and suggests that ulipristal
acetate may be at least as effective as levonorgestrel for EC.
Table 18 Study 507: pregnancy rates
50-mg UPA LNG Difference

(n = 773) (n = 773) pUPA pLNG
Number pregnant 7 13 -
Percent pregnant (%) 0.91 1.68 -0.78
Confidence intervals 0.36, 1.86 0.90, 2.86 -2.41, 0.77
Comments UL95%CI = 1.86 < 4% UL95%CI = 2.86 < 4% UL95%CI = 0.77% < 2%
Better than the clinical Better than the clinical Primary analysis: Far below
interest limit of 4% interest limit of 4% the unacceptable difference
5.2.2 Study 508
A total of 1026 subjects were enrolled and randomized within 72 h of unprotected intercourse in this
dose/formulation exploration study: 214 to the 10-mg treatment arm that was discontinued, 399 to 10-

May 2010 Page 52 of 108
mg micronized drug and 413 to the 50-mg formulation (Table 19). The 10-mg non micronized
treatment arm was prematurely stopped by the DSMB for futility (11 pregnancies out of 214 women).
Total Evaluable Subjects Completing the Study = 952
Overall, for the 10- (micronized) and 50- (unmicronized) mg doses, respectively, 365 and 384 subjects
were included in the primary efficacy analysis. The treatment groups were comparable at baseline in
terms of demography and baseline characteristics (see Table 45 in Appendix 2).
Efficacy results are presented in Table 19. There were proportionally more pregnancies in the 10-mg
micronized group (2.74%, 95% CI: 1.32-4.98) than in the 50-mg group (1.30%, 95%CI: 0.42-3.02).
The primary efficacy analysis was negative, meaning that a difference in the efficacy of 10-mg with
respect to 50-mg is compatible with an unacceptable difference of 2.5%. Moreover it has to be noted
that the pregnancy rate of 10 mg is compatible with a rate beyond the clinical interest limit of 4%. For
these reasons, 10 mg was not retained in subsequent Phase 3 trials.
Table 19 Study 508: pregnancy rates
10-mg UPA 50-mg UPA Difference

(n = 365) (n = 384) P10mg p50mg
Number pregnant 10 5
Percent pregnant (%) 2.74 1.30 1.44
Confidence intervals 1.32, 4.98 0.42, 3.02 -0.66, 3.82
Comments UL95% CI = 4.98 > 4% UL95% CI = 3.02 < 4% UL95% CI = 3.82% > 2.5%
True PR may be above the Better than the clinical Primary analysis: Difference
interest limit of 4% (not interest limit of 4% is compatible with the
statistically better than 4%). unacceptable difference limit

May 2010 Page 53 of 108
5.3 Disposition and demographics in Phase 3 studies
In Study 509, among the 1,623 subjects who provided informed consent and enrolled into the study,
1,533 were treated and included in the ITT population. A total of 1,241 subjects were eligible for the
mITT population and 1,244 for the mITT2 population (Figure 14). A scheduled interim analysis was
performed on first 900 mITT subject enrolled.
N=1533
ITT
N=190
- Not known pregnancy status after EC
intake n=106
- Repeat enrollments n=84
N=1343
ITT Completers
N= 99
- Age>35 n=90
- no UPI reported at screening n=9
N=1244
mITT2
N=3
- Pregnancy not compatible with a
treatment failure n=3
N=1241
mITT
Table 20 summarizes the demographic characteristics of subjects enrolled in Study 509.

May 2010 Page 54 of 108
Table 20 Demographics of Study 509 population (n=1533)
Age (years)
- Mean SD 24.4 6.1
- Range 18-50
- 16 - 20 446 (29.1%)
- 21 25 611 (39.9%)
- 26 30 258 (16.8%)
- 31 35 119 (7.8%)
- 36 99 (6.5%)
Race, n (%)
- White 921 (60.3%)
- Black or African American 328 (21.5%)
- Other (including Asian, Hawaiian and Other Pacific Islander ) 279 (18.3%)
Body mass index (kg/m2)
- Mean SD 25.3 6.2
Average menstrual cycle length, days (range) 29.0 (24 35)
% women with regular periods in the previous year 96.0%
Average bleeding days 4.7
(% of women with)
- intermenstrual bleeding 3.3%
- amenorrhea or oligomenorrhea 7.1%
% women with previous pregnancy 52.4%
% couples using male condoms within 3 months prior to inclusion 71.7%
% women having used EC in the past 52.5%
Number of acts of unprotected intercourse prior to enrollment within the
treatment cycle
(% of women with)
- 0 intercourse 0.6%
- 1 intercourse 84.9%
- 2 intercourses 11.2%
- 5 or more intercourses 0.2%
Time elapsed between intercourse and treatment
(% of women enrolled in)
- 48-72 h 69.2%
- 73-96 h 32.9%
- 97 h 13.1%
In Study 513, 2,321 subjects were screened, signed informed consent and were enrolled into the study
and 2,221 were randomized and treated (Figure 15). A scheduled interim analysis was performed on
the first 1,200 mITT subjects enrolled within 72 h after unprotected intercourse (ulipristal acetate, 596;
levonorgestrel, 604). Overall 1,694 mITT subjects (ulipristal acetate, 843; levonorgestrel, 851) were
analyzed for primary efficacy within the 72-h time window, and 1,893 were analyzed for secondary
efficacy in the 120-h time window. Six patients were enrolled 120 h and more after unprotected
intercourse and were not included in mITT analyses. However none of them become pregnant.

May 2010 Page 55 of 108
ITT
N=2221
ITT UPA ITT LNG

N=1104* N=1,117*
N=91 N=79
- Pregnancy status not known after EC - Pregnancy status not known after EC
intake n=77 intake n=57
- Repeat enrollments n=14 - Repeat enrollments n=22
ITT Completers ITT Completers

N=1013 N=1,038
N=71 N=78
- Age>35 n=69 - Age>35 n=76
- Pregnancy identified as having - Pregnancy identified as having
started before EC intake n=2 started before EC intake n=2
mITT2 mITT2
N=942 N=960
N=1 N=2
- Pregnancy not compatible per DSMB - Pregnancy not compatible per DSMB
n=1 n=2
mITT mITT Interim mITT mITT Interim

N=941 N=596 N=958 N=604
* A subject enrolled twice but into a different treatment group, was counted as independent for each treatment group, but
only once for overall

May 2010 Page 56 of 108
Table 21 summarizes the demographic information of subjects enrolled in Study 509.
Table 21 Demographics of Study 513 population
UPA 30mg LNG 1.5mg

N = 1,104 N = 1,117
Age (years)
- Mean SD 24.5 6.1 25.9 6.5
- Range 16-52 16-55
- 16 - 20 347 (31.4%) 328 (29.4%)
- 21 25 362 (32.8%) 364 (32.6%)
- 26 30 215 (19.5%) 229 (20.5%)
- 31 35 108 (9.8%) 113 (10.1%)
- 36 72 (6.5%) 83 (7.4%)
Race, n (%)
- White 804 (72.8%) 809 (72.4%)
- Black or African American 210 (19.0%) 207 (18.5%)
- Other (including Asian, Hawaiian and Other Pacific Islander ) 90 (8.2%) 101 (9.1%)
- Mean SD 25.3 5.9 25.2 5.7
Average menstrual cycle length, days (range) 28.7 (24 35) 28.8 (23 40)
% women with regular periods in the previous year 98.6% 98.7%
Average bleeding days 4.7 4.7
% of women with:
- intermenstrual bleeding 0.8% 1.3%
- amenorrhea or oligomenorrhea 2.5% 2.7%
% women with previous pregnancy 47.3% 47.8%
% couples using male condoms within 3 months prior to inclusion 82.1% 83.7%
% women having used EC in the past 54.9% 55.7%
Number of acts of unprotected intercourse prior to enrollment
within the treatment cycle
(% of women with)
- 0 intercourse 0.1 0.3
- 1 intercourse 89.4 88.5
- 2 intercourses 7.5 9.0
- 5 or more intercourses 0.0 0.0
Time elapsed between intercourse and treatment (% women)
- 24 h 33.0 35.0
- 25-48 h 35.0 34.0
- 48-72 h 22.0 20.0
- 73-96 h 7.0 8.0
- 97 h 3.0 3.0

May 2010 Page 57 of 108
5.4 Primary efficacy results
Both trials were conclusive with respect to the protocol and statistical analysis plan definition of study
success.
In the mITT population of the open-label Study 509, the observed pregnancy rate after taking 30-mg
ulipristal acetate between 48 and 120 h after unprotected intercourse was 2.10% (95% CI: 1.41% -
3.10%), which was statistically significantly lower than the estimated expected pregnancy rate in the
absence of EC of 5.53% (Table 22). The upper limit of the 2-sided 95% CI of the observed pregnancy
rate (3.10%) was also below the clinical interest limit (4%). The primary objective of the study was
therefore fully met.
Sensitivity analyses conducted on the mITT2 and ITT completer populations also produced results
consistent with study success criteria; observed pregnancy rates in these populations were 2.33% (95%
CI: 1.60% - 3.37%) and 2.17% (95% CI 1.49% - 3.15%), respectively.
The planned interim analysis performed on 900 mITT subjects did not meet the success criteria and the
trial proceeded up to the final planned sample size.
Table 22 Study 509: Comparison of observed vs. expected pregnancy rates
mITT population
(primary efficacy variable)
(n = 1241)
Observed pregnancies (n) 26
Expected pregnancy rate (%) 5.53
Observed pregnancy rate (%; 95% CI) 2.10 (1.41 - 3.10)
Comments: UL95% CI = 3.10 < 4% < 5.53%
Efficacy significantly better than the unacceptable rate (5.53%) and
clinical interest limit (4%)
In the randomized comparative Study (513), the interim analysis performed on 1200 mITT subjects
treated within 72 h was positive and recruitment was stopped as planned. Because the entire sample
had accrued by the time the interim database was locked, the final number of subjects included in the
mITT analyses was much larger than for the interim analysis. The observed pregnancy rate after taking
30-mg ulipristal acetate between 0 and 72 h after unprotected intercourse was 1.78% (95% CI: 1.04% -
2.98%), which was statistically significantly lower than the estimated expected pregnancy rate in the
absence of EC of 5.54% (Table 23). The upper limit of the 2-sided 95% CI of the observed pregnancy
rate (3.10%) was also below the clinical interest limit (4%). The primary objective of the study was
therefore fully met.
Sensitivity analyses conducted on the mITT2 and ITT completer populations also produced results
consistent with study success criteria; observed pregnancy rates in these populations were 1.90% (95%
CI 1.13% 3.12%) and 2.20% (95% CI 1.39% 3.43%), respectively.

May 2010 Page 58 of 108
Table 23 Study 513: Comparison of observed vs. expected pregnancy rates
Study 513 Ulipristal acetate Levonorgestrel

mITT population (n=843) (n=851)
0-72 h
Observed pregnancies (n) 15 22
Expected pregnancy rate (%) 5.54% 5.43%
Observed pregnancy rate (%; 95% CI) 1.78 (1.04 2.98) 2.59 (1.68 3.94)
Comments: UL95% CI = 2.98 < 4% < 5.54% UL95% CI = 3.94 < 4% < 5.43%
Better than the unacceptable rate Better than the unacceptable rate
(5.54%) and clinical interest limit (5.43%) and close to clinical interest
(4%) limit (4%)
5.5 Additional efficacy analyses
5.5.1 Efficacy over time
Individual Phase 3 studies
A secondary efficacy analysis planned in both of the Phase 3 trials was the evaluation of the trend in
pregnancy rates over time (from the time of unprotected intercourse to EC treatment).
Pregnancy rates were calculated for each 24-h interval, and the odds ratio compared to the previous
24-h interval was estimated. In neither study was a significant increase or decrease observed between
two consecutive days.
Table 24 summarizes the efficacy rate over time in the two Phase 3 studies (509 and 513).
Table 24 Studies 509 and 513: Pregnancy rates by time from unprotected intercourse to ulipristal acetate treatment
Time from intercourse

< 24 24-48 48-72 73-96 97-120
to treatment (h)
Study # 513 509 513 509 513 509 513 509 513 509
N of subjects included 312 329 203 693 63 390 34 158
N of observed
5 7 3 16 0 8 0 2
pregnancies
Pregnancy rate (%) 1.6 2.13 1.48 2.30 0.00 2.04 0.00 1.26
Odds ratio* (95% CI) NA 1.33 0.69 NA 0.00 0.89 NA 0.61
(0.42-4.25) (0.18-2.70) (0.38-2.09) (0.13-2.92)
* Odds ratio at a given time interval is relative to the previous 24-h time interval.
Pooled analyses
The efficacy results for the pooled Phase 3 population by 24-h interval from unprotected intercourse to
treatment are summarized in Table 25. The trend over time in pregnancy rates was assessed on an
exploratory basis with pooled data through a trend test and a logistic regression using time from
unprotected intercourse as a quantitative explanatory variable. There was neither effect of time as a
quantitative variable (p = 0.6251, logistic regression) nor trend over time (p >> 0.05). Moreover, the

May 2010 Page 59 of 108
upper bound of the 95% confidence interval of the observed pregnancy rate was consistently lower
than the expected rate (Table 25). Ulipristal acetate therefore appears efficacious up through 120 h
after intercourse.
Table 25 Pooled Phase 3 studies: Pregnancy rates by time from unprotected intercourse to ulipristal acetate
treatment
Hours since unprotected N of subjects Observed PR, % Expected PR, %

intercourse mITT pooled Phase 3 (95 % CI)
0-24 313 1.60% 4.83%
(0.57-3.79)
> 24-48 338 2.07% 5.88%
(0.92 -4.30)
> 48-72 881 2.16% 6.02%
(1.36-3.37)
> 72-96 455 1.76% 5.26%
(0.83-3.49)
> 96 193 1.04% 5.49%
(0.04-3.94)
Total 2,180 1.88% 5.62%
(1.38-2.55)
5.5.2 Comparative efficacy vs. levonorgestrel
Phase 2/3
As reviewed above, in the comparative Study 507 the observed pregnancy rate in the ulipristal acetate
group was lower than that of levonorgestrel, but the difference did not reach the significance level
(unadjusted OR = 0.53, 95% CI: 0.20 1.31). If we applied a posteriori the limit retained in Phase 3
(OR=1.6), ulipristal acetate was non inferior to levonorgestrel as an emergency contraceptive.
Phase 3
Phase 3 Study 513 included a levonorgestrel comparator arm and was powered to assess non-
inferiority of ulipristal acetate to levonorgestrel for women treated up to 72 h after unprotected
intercourse. This analysis was a secondary endpoint in the study protocol.
The pregnancy rates in the two groups are presented in Table 26. They were compared using an odds
ratio calculated via logistic regression, with a non-inferiority margin of 1.6. Ulipristal acetate was non-
inferior to levonorgestrel when used as EC within 72 h of unprotected intercourse (OR 0.68, 95% CI:
0.35 - 1.31). In the 72-120-h interval, no pregnancies were observed in the ulipristal acetate group
versus three pregnancies in the levonorgestrel group. The unadjusted odds ratio of pregnancy
(ulipristal acetate vs. levonorgestrel) during the overall 0-120-h time interval was 0.59 (0.31, 1.14).

May 2010 Page 60 of 108
Table 26 Study 513: Comparative pregnancy rates for treatment

within 72 h or 120 h of unprotected intercourse
Pregnancy rate (%) [95% CI]

Ulipristal acetate Levonorgestrel
0-72 h mITT 1.78 (1.04, 2.98) 2.59 (1.68, 3.94)
(n= 1,694)
0-120 h mITT 1.60 (0.93, 2.67) 2.62 (1.75, 3.89)
(n= 1,893)
Meta-analysis
Two efficacy trials included a levonorgestrel comparator arm (Study 507 and Study 513), and post-hoc
analyses were performed on the pooled data from these two trials. Both trials had a similar design,
although the drug formulations differed between the two trials (see individual study descriptions in
Ssection 4.8.1). Subjects eligible for primary analysis of Study 507 (n=1,546) and Study 513 (n=1,899)
were combined for a total of 3,445 women exposed (ulipristal acetate n=1,714, levonorgestrel
n=1,731). A total of 60 pregnancies (ulipristal acetate n=22, levonorgestrel n=38) were observed in
this set of subjects.
The odds ratios (and corresponding 95% CI) adjusted for conception probability, BMI and further
unprotected intercourse comparing pregnancy rates with ulipristal acetate vs. levonorgestrel are
displayed for each study and for the meta-analysis in Figure 16.
Figure 16 Adjusted odds ratio of pregnancy with ulipristal acetate compared to levonorgestrel (OR and 95% CI)
in individual studies and for meta-analysis
Odds Ratio (UPA/LNG) & 95% CI
1 (UPA = LNG)
0.188 0.506 1.254

Study 507 (0-72h)
0.308 0.619 1.210

Study 513 (0-72h)
0.330 0.578 0.991

Meta-analysis (0-72h)
0.109 0.345 0.928

Meta-analysis (0-24h)

May 2010 Page 61 of 108
5.5.3 Efficacy in population subgroups and per intrinsic or extrinsic factors
Intrinsic factors
Table 46 in Appendix 3 summarizes efficacy analyses and comparison of efficacy for different sub-
populations from the two pivotal Phase 3 studies per intrinsic factors. As indicated in this table, there
was no effect of age, region, race or pregnancy history on pregnancy rate after ulipristal acetate
treatment; only increasing BMI was found to be positively correlated with pregnancy risk, without
reaching statistical significance in the pooled Phase 3 analysis. As the mITT population excludes
women age 36 and more, exploratory analyses by age category were performed on a broader
population (ITT completers pooled Phase 3).
The effects of BMI were explored using the meta-analysis database and WHO categories for BMI.
BMI was found to be significantly related to pregnancy risk, regardless of the treatment group
(p<0.0001). For underweight women and normal BMI (BMI <25), the comparative efficacy of
ulipristal acetate versus levonorgestrel as measured by odds ratio was 0.81 (95% CI: 0.37-1.73). For
overweight and obese grade I women (BMI 25-35) the odds ratio was 0.31 (95% CI: 0.11-0.74), and
for more obese women (BMI >35) the odds ratio was 1.02 (95% CI: 0.23-4.44).
Extrinsic factors
Table 47 in Appendix 3 summarizes efficacy analyses and comparison of efficacy for different sub-
populations from the two pivotal Phase 3 studies (Studies 509 and 513) per extrinsic factors.
Repeat users
Pregnancy rates were assessed in subjects in the Phase 3 trials (n=84 subjects for a total of 93 protocol-
allowed repeat participations) who took ulipristal acetate a second time in the same cycle and those
who took again ulipristal acetate in subsequent cycles. None of these repeat users became pregnant
during subsequent intake.
Post treatment intercourse (further unprotected intercourse)
In the Phase 3 studies, a total of 130 subjects reported subsequent unprotected intercourse after
ulipristal acetate intake. As shown in Table 47 in Appendix 3, in these subjects, the observed
pregnancy rate was significantly higher than in those having had no subsequent unprotected
intercourse.
Food interaction
Data on last food intake prior to study drug was collected in a subset of subjects (n=1,184) included in
the Phase 3 pivotal studies (Table 47 in Appendix 3). Pregnancy rates were compared between women
who reported having eaten within two hours prior to treatment intake versus those who reported having

May 2010 Page 62 of 108
eaten only earlier. There was no significant effect of food consumption prior to ulipristal acetate intake
on pregnancy rate in the Phase 3 trials.
A specific food interaction study (Study 512) was conducted, in which the PK profile of ulipristal
acetate and its main monodemethylated metabolite CDB-3877 was evaluated over 168 h after single
administration of a 30-mg dose either under fasted conditions or after a high-fat breakfast. Dosing with
food significantly reduced the absorption rate of ulipristal acetate (40-45% lower Cmax and by a delay
in Tmax of about 1.5 h for both ulipristal acetate and metabolite) but increased the extent of absorption
(20-25% increase in AUC of both ulipristal acetate and metabolite).
Concomitant diseases and concomitant medications
The impact of pharmacologically-relevant concomitant diseases and medications and subsequent EC

use was reviewed descriptively, with specific emphasis on asthma and glucocorticoid treatments
(given the binding affinity of the compound for the glucocorticoid receptor) and drugs and diseases
affecting gastric pH (because the drugs dissolution is pH-dependent).
Altogether, 57 subjects reported asthma. Among them, two became pregnant, one while treated with
prednisone, and the other with fluticasone. No asthma worsening was reported as a treatment-emergent
AE except in one subject who reported several asthma attacks after ulipristal acetate treatment.
Twenty-six subjects were reported to be taking antacid drugs while receiving ulipristal acetate
treatment: none became pregnant.
In the Phase 3 studies, 46 subjects who had further acts of unprotected intercourse after ulipristal
acetate intake used levonorgestrel emergency contraception (commercially-available products) later in
the same cycle. These women had a lower pregnancy rate (4.35%) than that reported for women with
subsequent unprotected intercourse who did not use levonorgestrel emergency contraception (7.14%),
which indicates that prior ulipristal acetate use does not interfere with levonorgestrel action.
5.6 Generalizability of efficacy data
The eligibility criteria in the efficacy trials were broad and the studies were conducted primarily in the
US. The demographic characteristics of the populations are representative of US women who are
candidates for EC.
The objective of the clinical development program was to evaluate pregnancy prevention by measuring
the pregnancy rate in women who received ulipristal acetate compared with control agents. The single
most important predictor of pregnancy risk is the timing of intercourse with respect to ovulation
(Dunson et al, 2001). Women enrolled in the efficacy trials reported regular menstrual cycles with
little inter-cycle variation in cycle length, so the distribution of cycle day of intercourse in the study
population can be approximated to overall pregnancy risk.

May 2010 Page 63 of 108
The frequency of unprotected intercourse in the study populations peaked at mid-cycle in all efficacy
trials. With respect to EC, women who do not wish to become pregnant may select to take EC after
what they perceive to be the most at-risk acts of intercourse, those that occur close to cycle day 14 (the
presumed day of ovulation). That being said, the pattern observed in these studies is similar to the
results of a recent observational study in a population of women using effective non-hormonal
methods of birth control which showed that the frequency of intercourse peaks during the fertile
window (the six days leading up to and including the day of ovulation), seemingly for biological
reasons (Wilcox et al, 2004) including fluctuations in womens libido (Dennerstein et al, 1994),
patterns of pheromone production (McCoy et al, 2002), or an acceleratory effect of intercourse on
ovulation, as observed in animals (Bakker et al, 2000). This suggests that the population included in
the efficacy trials presents an overall pregnancy risk that may be similar to that of the general
population.
Varying patterns of intercourse and ovulation can introduce biases in the calculation of EC efficacy.
When efficacy is based on measures that rely on the cycle day of intercourse to assess pregnancy risk,
intra-individual variability in the cycle day of ovulation may be a confounding factor. For example,
women therefore may not report intercourse that occurred earlier or later in the cycle because it was
presumably not at risk. Indeed, in the two Phase 3 studies, 15 of the women who became pregnant
after ulipristal acetate treatment had reported an index unprotected intercourse having taken place
outside the presumed fertile period, at a time when the theoretical risk of pregnancy (and therefore
the conception probability used in the estimation of the expected pregnancy rate) was nil.
The primary efficacy parameter used in the efficacy trials was the pregnancy rate, calculated as the
number of pregnancies after administration of study drug, divided by the number of subjects whose
post-treatment pregnancy status (pregnant/not pregnant) was known. This parameter is not at risk of
recall bias and does not rely on any assumptions about the fertile window and the expected pregnancy
rate. However, because it is impossible to undertake placebo-controlled studies in this indication, the
observed pregnancy rate was compared to an expected pregnancy rate estimated according to
conception probabilities provided by Trussell et al (1998). In addition, an objective pregnancy rate of
4% was established as the clinical interest limit, and study success required positive outcome of both
of these analyses. All of the trials were conclusive with respect to the protocol-defined efficacy
thresholds.

May 2010 Page 64 of 108
6 CLINICAL SAFETY
6.1 Key points
The safety database comprises results from clinical trials in over 4,700 women exposed to single
doses of ulipristal acetate up to 200 mg and repeated dosing for up to 84 days.
The most frequently reported adverse events were headache, nausea, dysmenorrhea and abdominal
pain, a profile similar to that reported in the levonorgestrel comparison groups in randomized trials.
Of the nine serious adverse events reported in the clinical development program (single dose
administration), one (dizziness in Study 509) was considered possibly related to ulipristal acetate
treatment.
Ulipristal acetate treatment increased menstrual cycle length by a median of 1 day in healthy
normal women.
Laboratory safety parameters were measured in a subset of subjects, but only a few sporadic
changes were detected and did not suggest a specific treatment effect.
Post-marketing safety surveillance in Europe did not detect any safety signal in the first year since
marketing authorization.
collected in clinical trials (n=93) or via post-marketing surveillance (n=18). Many ended in
elective termination, data on birth outcome is limited.
6.2 Exposure to ulipristal acetate
6.2.1 Sources of information and overall extent of exposure
a. Single dose administration
The safety profile of ulipristal acetate (single dose administration) is supported by data from eight
pharmacokinetic / pharmacodynamic studies and the four efficacy trials. Overall, 4,636 subjects were
evaluated for safety of ulipristal acetate (single dose administration). Among them, 2,537 (54.7%) had
received the to-be-marketed 30-mg tablet (see Figure 17 and details by study in Table 48 of Appendix
4).
In Phase 1 Study 501, the 10 subjects were enrolled three times. Four multiple enrollments were
reported in the Phase 2/3 studies. In the Phase 3 studies, 84 women received ulipristal acetate more
than once (75 enrolled twice and 9 more enrolled three times).

May 2010 Page 65 of 108
In addition, safety information was obtained from post-marketing surveillance in Europe covering the
period from May 15, 2009 to May 12, 2010.
Figure 17 Number of subjects exposed to single dose of ulipristal acetate during the clinical development in EC
Safety database UPA

(single dose administration for EC)
N = 4,636
Phase 1 Phase 2/3 Phase 3

N = 241 N = 1,858 (30-mg tablet)
N = 2,537
1-mg UM capsule 10-mg UM capsule

N=6 N = 214
10-mg UM & micronized capsule/tablet 10-mg micronized capsule

N = 40 N = 399
50-mg UM capsule 50-mg micronized capsule

N = 31 N = 1,245
100-mg UM capsule
N = 31
200-mg UM capsule
N=6
30-mg tablet
N = 127

May 2010 Page 66 of 108
b. Repeat administration
A single pharmacodynamic study (Study 510) evaluated the dose-response effects of continuous
administration over twelve weeks of low dose (2.5 mg, 5 mg or 10 mg) ulipristal acetate in comparison
to placebo on the hypothalamic-pituitary-gonadal axis and the endometrium of 46 women of whom 35
received ulipristal acetate.
Additional studies performed by other sponsors in other indications: studies are underway in the
treatment of uterine fibroids and for long-term contraception in non-oral formulations. Data has been
made available to HRA Pharma through annual safety reports prepared by the sponsors.
6.2.2 Collection and analysis of safety data
Adverse events (AE)
All AEs, whether serious or not, were collected by open questioning from the time the subject gave her
informed consent up to the end of the study in all studies. Each AE was evaluated for duration,
intensity and association with the study medication and other causes. The action taken and the subject
outcome were also recorded. The intensity of the AE was characterized as mild, moderate, or severe.
All AEs were coded and classified by MedDRA System Organ Class / Preferred Term.
In the two Phase 2/3 supportive efficacy trials, immediately after treatment intake, subjects were asked
to fill in a three-day diary card with a yes/no response to a predefined checklist of events including
nausea, vomiting, breast tenderness, fatigue, lower abdominal pain, diarrhoea and headache. The daily
severity of nausea and vomiting were also recorded. Vaginal bleeding and coital data were recorded by
subjects in a separate calendar and collected at each follow-up visit. All experienced AEs were
recorded at each follow-up visit. In the pivotal Phase 3 efficacy trials, subjects were asked to record
any AEs experienced between treatment and follow-up in a home diary calendar (approximately one
month).
Serious AEs presented exclude events reported in baseline or pre-treatment phases in

pharmacodynamic studies.
Specific monitoring
Cycle length and bleeding patterns of the treatment cycle were evaluated in the five pharmacodynamic
studies and in all four efficacy trials. Menstrual calendar data were used to evaluate cycle length and
bleeding patterns of the cycle in which study drug was administered. Menstrual cycle length was
defined as the number of days from the first day of bleeding up to and including the day before the
next menses.
Characteristics of the post-treatment cycle were assessed in four pharmacodynamic studies.

May 2010 Page 67 of 108
Systematic vaginal ultrasonographic examination was performed in all five pharmacodynamic studies
to document follicular development.
In studies 506 and 510, endometrial biopsies were obtained to evaluate endometrial histology.
Laboratory parameters
The clinical safety database includes biochemical and haematological evaluation performed in a total
of nine studies, as indicated in Table 27. In all pharmacodynamic studies, blood samples to assess
hypothalamo-pituitary-ovarian and adrenal axes were taken, and the results are discussed along with
pharmacodynamic results in Section 4.6 above.
Table 27 Laboratory evaluations performed during clinical development of ulipristal acetate
Study/ Phase Parameters assessed Timing of assessment

501 Blood chemistry, haemogram, kidney and Prior to and after the study
Phase 1 liver function tests
503 Urinalysis, haemogram, blood chemistry, Baseline and on days 1, 2 and 7

Phase 1 kidney and liver function tests
504 Full blood count (leucocytes, erythrocytes, At screening and on day 28,
Phase 1 haemoglobin, haematocrit, platelets,
neutrophils, eosinophils, and lymphocytes),
clinical chemistry profile (creatinine, total
bilirubin, GGT, AST, and ALT)
505 and 506 Blood chemistry, complete blood count and 5-7 days after dosing
Phase 1 hepatic test
511 Blood count (CBC), chemistry profile, At screening and at end-of-study visit
Phase 1 renal and liver function and lipids (total
cholesterol, HDL, LDL, triglycerides) were
assessed
512 Blood count (CBC), chemistry profile, At screening (before treatment intake) and at end-of-
Phase 1 renal and liver function study in all subjects
516 Blood count (CBC), chemistry profile, At screening (before first treatment intake), at the
Phase 1 renal and liver function were assessed beginning of period two (before second treatment
intake), and at end-of-study
510 Liver function, electrolytes profile, At baseline, during the third treatment cycle and
Phase 1 (repeat creatinine, blood sugar, total cholesterol post-treatment
dose) and triglycerides
509 Blood count (CBC), chemistry profile, At screening and at end-of-study visit
Phase 3 renal and liver function, lipids (total
cholesterol, HDL, LDL, triglycerides)

May 2010 Page 68 of 108
Pregnancy follow-up
All study protocols stipulated that pregnancies observed during clinical trials were to be followed up to
determine outcome (spontaneous or elective termination or birth). Details regarding birth outcome
were recorded.
Pooled safety analysis
ITT populations of the two Phase 3 Studies 509 and 513 conducted with the to-be-marketed 30-mg
tablet were pooled for integrated safety analysis to assess overall incidence of AEs, impact on
menstrual cycle and safety profile with respect to intrinsic and extrinsic factors.
6.3 Safety from single dose exposure
6.3.1 Serious adverse events
Overall nine SAEs were reported in subjects administered single doses of ulipristal acetate; they are
summarized in Table 28. No death occurred during the clinical development program.
Table 28 Serious Adverse Events reported in subjects administered single dose ulipristal acetate, with causality
assessment
To-be-marketed 30-mg tablet 50-mg capsule

Phase 3 Phase 1 Phase 2/3
Study N 509 513 504 512 507
(n) (1533) (1104) (20) (19) (832)
Urinary tract infection 1 (UR)
Corneal ulcer 1 (UR)
Dizziness 1(PR*)
Seizure 1 (UR)
Bacterial pneumopathy 1 (UR)
Pilonidal cyst 1 (UR)
Kidney infection 1 (UR)
Pelvic inflammatory disease 1 (UR)
Optic nerve hypoplasia 1 (UR)
*Causality assessment: UR: unrelated, PR: possibly related
a. Phase 1 studies
Two SAEs were reported in Phase 1 studies for single dose administration: one in Study 504 and one
in Study 512. The SAE observed in Study 504 was reported in a 29-year-old Caucasian woman who
received 30-mg ulipristal acetate on 18 December 2007 and experienced fever, cough, and thoracic
pain on 2 January 2008. Severe bacterial pneumopathy was diagnosed and the subject was
hospitalized. The SAE had resolved at the end of January and was considered by the investigator as not
related to the study medication.

May 2010 Page 69 of 108
The SAE observed in the Study 512 was reported in a 20-year-old Caucasian woman without any
medical history who attended the screening visit on 19 June 2008. Laboratory tests were within normal
limits. She received 30-mg ulipristal acetate in fasted conditions on 19 June 2008. On 6 July 2008, a
pilonidal cyst was diagnosed and the investigator took the decision to discontinue the subject from the
study. The cyst was uneventfully removed on 10 July 2008. The investigator considered that this SAE
was not related to ulipristal acetate intake.
b. Phase 2/3 supportive efficacy trials
Two SAEs were reported in the ulipristal acetate group in Study 507, and none were reported in Study
508. In Study 507, a 21-year old woman who received 50-mg ulipristal acetate on 28 October 2000
was diagnosed with a kidney infection in December 2000. The SAE resolved after antibiotic treatment
and was not considered by the investigator to be related to ulipristal acetate. The second SAE occurred
in a 22-year old woman who was diagnosed with pelvic inflammatory disease in September 2000. This
subject had received 50-mg ulipristal acetate in August 2000. The SAE resolved after antibiotic
treatment and was not considered by the investigator to be related to ulipristal acetate.
c. Phase 3 pivotal efficacy trials
In Study 509, one SAE was reported in a 21-year old woman who had a history of seizures beginning
in 2005. She experienced one seizure the week prior to her enrollment in 2007 and 3 seizures one day
after the intake of a single dose of 30-mg ulipristal acetate. The subject was hospitalized and was
diagnosed with ecstasy-related seizures. The SAE resolved and was not considered by the
investigator to be related to the study medication.
In Study 509, a subject who took ulipristal acetate on cycle day 10 subsequently became pregnant and
delivered normally a baby who was later diagnosed with optic nerve hypoplasia. This case was
declared as a SAE when reported to the site after the end of the study and was not considered as related
to the study medication by the investigator.
In Study 513, three SAEs were reported during the study (a case of urinary tract infection, a case of
right contact lens related corneal ulcer and a case of dizziness).
Only one SAE (dizziness) was considered possibly related to the study drug. An 18-year-old female
patient took one tablet of ulipristal acetate on 07 November 2008 at noon. On the same day, she
experienced severe vertigo resulting in incapacity, she was unable to walk. She was also treated with
Excedrin (acetaminophen, aspirin, caffeine) due to concomitant headache. The patient was
subsequently reported as recovered from vertigo and investigator assessed the causal relationship
between study drug and vertigo as suspected.

May 2010 Page 70 of 108
6.3.2 Individual study results
a. Phase 1 studies
Ulipristal acetate was well tolerated at all doses. The most common AEs are summarized in Appendix
5 (Table 49).
Laboratory parameters were measured in seven Phase 1 single intake studies and findings are
summarized in Appendix 5 (Table 50). No clinically meaningful finding was identified.
Post-treatment cycle characteristics were assessed in four Phase 1 studies. In studies 503, 505 and 506,
there was no significant mean cycle length change in treatment cycles. In Study 511, treatment cycle
length was prolonged by a mean of 2.5 days after ulipristal acetate intake. Post-treatment cycles were
ovulatory for all subjects in Study 503 and 506, and for almost all subjects in Study 511 (31/34).
Persistent follicles recorded as ovarian cysts were observed at systematic ultrasonographic

examination during treatment cycles in Phase 1 studies (Table 29). In most cases, follicle size was
between 15 and 30 mm, likely corresponding to pre-ovulatory unruptured follicles.
Table 29 Ultrasound findings recorded as ovarian cysts during Phase 1 studies with ulipristal acetate
Study # Sizes Doses Number of Outcome

subjects
505 15-33 mm Placebo 2 Spontaneous resolution
UPA 10-mg 1 Rupture
UPA 50-mg 4 Spontaneous resolution
UPA 100-mg 4 Spontaneous resolution for all except one 16 mm
cyst persistent at 3 months
506 12-24 mm Placebo 3
UPA 10-mg 4
Spontaneous resolution
UPA 50-mg 2
UPA 100-mg 1
Two pregnancies were observed in Studies 503 (intake of 200-mg unmicronized ulipristal acetate) and
506 (intake of 10-mg unmicronized ulipristal acetate): both resulted in normal live births.
b. Phase 2/3 supportive efficacy trials
- Study 507
This study compared the efficacy of ulipristal acetate (50mg) with levonorgestrel (2*0.75mg) for
emergency contraception up to 72h after intercourse.
Adverse events reported during Study 507 are indicated in Appendix 6 (Table 51). In this study, 77%
of the subjects having taken ulipristal acetate (639/832) reported at least one AE. The most frequently
reported adverse events in each treatment group were fatigue and headache. No AEs leading to
discontinuation of the study treatment were reported.

May 2010 Page 71 of 108
More subjects experienced nausea in the ulipristal acetate treatment group (30% or 237 subjects) than
in the levonorgestrel treatment group (24% or 186 subjects). Of those who did experience nausea, most
did so on day 1 of study treatment (73-74%). The incidence of vomiting between the two treatment
groups did not differ (2%).
Subjects in both treatment groups had similar bleeding and spotting experiences. Relative to the
average cycle length reported by subjects on study entry, the treatment cycle was about 3 days longer
for ulipristal acetate subjects and about 2 days shorter following treatment with levonorgestrel.
Table 30 shows the pregnancies and their outcome observed in this study.
Table 30 Pregnancies and outcome, in Study 507
Treatment N of pregnancies () Pregnancy outcome

50-mg unmicronized UPA 12 (4) - 9 induced terminations
- 1 spontaneous miscarriages
- 2 lost to follow up
0.75-mg 2 levonorgestrel 14 (1) - 8 induced terminations
- 1 normal live birth
() number of pre-treatment pregnancies
- Study 508
This study compared the efficacy of different doses of ulipristal acetate (50-mg versus 10-mg) for
emergency contraception up to 72h after intercourse. The 10-mg dose formulation was changed from
unmicronized to micronized following an unacceptably high pregnancy rate.
Adverse events reported during Study 508 are indicated in Appendix 6 (Table 52). In this study, at
least 75% of subjects in each treatment group and overall experienced at least one AE. The three most
commonly reported AEs were headache, nausea and pelvic pain. There were no serious adverse events
and no AEs leading to discontinuation of the study was reported.
Subjects treated with 10-mg micronized ulipristal acetate experienced significantly more nausea than
subjects treated with 50-mg ulipristal acetate during the study period (p<0.01) as well as within the
first 24 hours of treatment (on study days 2 and 3, no difference in incidence). Subjects treated with
50-mg ulipristal acetate experienced more diarrhea on day 1 than did subjects treated with 10-mg
micronized ulipristal acetate. Two treatment groups did not differ with respect to the frequency of
other AEs.
The mean change in cycle length from the cycle prior to enrollment to the study cycle was comparable
across the two treatment groups (1.4 days 10-mg micronized, 2.0 days 50-mg).

May 2010 Page 72 of 108
Dose of UPA N of pregnancies () Pregnancy outcome

10-mg unmicronized 13 (2) - 8 induced terminations
- 3 lost to follow up**
10-mg micronized 11 (1) - 9 induced terminations
- 1 lost to follow-up**
50-mg unmicronized 5 (0) - 4 induced terminations
c. Phase 3 pivotal efficacy trials
- Study 509
This study assessed the efficacy of ulipristal acetate (30 mg) for emergency contraception 48-120h
after intercourse.
In Study 509, 876 (61.4%) of the subjects having received 30-mg ulipristal acetate experienced a total
of 2232 AEs, of which 49.6% were considered to be treatment related. The majority (89.1%) of the
AEs were mild or moderate in intensity and spontaneously resolved.
Table 32 shows the incidence of AEs reported between enrollment and study completion (approximate
duration of reporting of one month) in 1% of the ITT population independent of causal relationship
with study drugs in Study 509.

May 2010 Page 73 of 108
Table 32 Incidence of Adverse Events in 1% of ITT population subjects in Study 509
Number of subjects (%) 1533 (100)

At least one AE (%) 876 (61.4)
At least one SAE (%) 188 (8.4)
Most common AE (%)
Headache 269 (17.7)
Nausea 187 (12.2)
Abdominal pain 180 (11.7)
Dysmenorrhea 102 (6.7)
Fatigue 86 (5.6)
Dizziness 83 (5.4)
Pelvic pain 59 (3.8)
Abdominal pain upper 49 (3.2)
Nasopharyngitis 41 (2.7)
Back pain 37 (2.4)
Abdominal distension 32 (2.1)
Muscle spasm 31 (2.0)
Vomiting 28 (1.8)
Vaginal discharge 23 (1.5)
Mood swings 23 (1.5)
Migraine 19 (1.2)
Pain 19 (1.2)
Menorrhagia 19 (1.2)
Diarrhea 18 (1.2)
Somnolence 18 (1.2)
Acne 16 (1.0)
Breast tenderness 16 (1.0)
In this study, as shown in Table 33, treated subjects reported a mean increase of 2.9 days and a median
increase of 1 day from cycle length reported at screening. 80.8% of women had an increase of
menstrual cycle length of 7 days or less.

May 2010 Page 74 of 108
Table 33 Duration of treatment cycle in ITT population of Study 509
Duration of treatment menstrual cycle (days)

- mean (sd) 31.8 (10.2)
- median 30.0
- range 7.0 to 109.0
Change from average cycle length (days)
- mean (sd) 2.9 (10.1)
- median 1.0
- range -22.0 to 79.0
Percent subjects with treatment cycle change
7 days 80.8
>7 days 19.2
> 20 days 5.1
One ovarian cyst was observed in the study which spontaneously resolved during the treatment cycle.
In this study, 112 subjects have had clinical laboratory evaluation at screening and end-of-study. No
decrease in the mean haemoglobin value was observed. Only three subjects with normal values at
screening had haemoglobin values slightly below the lower limit of normal at the end of the study. One
subject with a normal hepatic panel at screening presented an isolated and moderate increase in ALT
(74, N<55) and in AST (88, N<45) twelve days after ulipristal acetate intake, which was not reported
as an AE. For six subjects, changes from screening in the laboratory test values were assessed by the
investigator as clinically meaningful and reported as AEs. These changes were considered by the
investigator as not related or with unknown relationship to the study medication.
N of pregnancies () Pregnancy outcome
29 (1) - 16 induced terminations

- 1 delivery of a baby with subsequent diagnosis of severely altered vision**
- 5 lost to follow-up*
* Lost to follow-up after pregnancy diagnosis ** Assessed as unrelated to UPA exposure
- Study 513
This study assessed the efficacy of ulipristal acetate (30-mg) for emergency contraception, in
comparison with levonorgestrel (1.5-mg).
In Study 513, 597 (54.1%) of the subjects having received 30-mg ulipristal acetate experienced 1506
AEs, of which 675 (44.8%) were considered treatment related; while 626 (56.0%) of the
levonorgestrel-treated subjects experienced 1629 AEs, of which 752 (46.2%) were considered

May 2010 Page 75 of 108
treatment related. The majority of the AEs (ulipristal acetate, 93.9%; levonorgestrel, 94.0%) were mild
or moderate in intensity and resolved spontaneously.
Table 35 shows the incidence of AEs in 1% of the ITT population independent of causal relationship
with study drugs in this study reported between inclusion and end of study (approximately one month).
Table 35 Incidence of Adverse Events in 1% of ITT population subjects in Study 513
UPA LNG
Number of subjects (N = 1,104) (N = 1,117)
At least one AE, n (%) 597 (54.1) 626 (56.0)
At least one SAE, n (%) 63 (5.7) 73 (6.5)
Most common AE, n (%)
Headache 213 (19.3) 211 (18.9)
Nausea 141 (12.8) 126 (11.3)
Dysmenorrhea 142 (12.9) 160 (14.3)
Fatigue 61 (5.5) 44 (3.9)
Dizziness 57 (5.2) 55 (4.9)
Abdominal pain 56 (5.1) 75 (6.7)
Abdominal pain upper 37 (3.4) 46 (4.1)
Back pain 35 (3.2) 27 (2.4)
Nasopharyngitis 31 (2.8) 32 (2.9)
Abdominal pain lower 21 (1.9) 35 (3.1)
Breast tenderness 20 (1.8) 19 (1.7)
Abdominal distension 17 (1.5) 14 (1.3)
Vomiting 17 (1.5) 12 (1.1)
Vaginal discharge 17 (1.5) 17 (1.5)
Diarrheoa 16 (1.4) 17 (1.5)
Seasonal allergy 14 (1.3) 9 (0.8)
Migraine 13 (1.2) 15 (1.3)
Somnolence 10 (0.9) 12 (1.1)
Pharyngolaryngeal pain 9 (0.8) 16 (1.4)
Figure 18 shows the comparative frequency (levonorgestrel vs. ulipristal acetate) of the most common
adverse events observed during this study.

May 2010 Page 76 of 108
Figure 18 Most frequent Adverse Events (3% of ITT population subjects), in Study 513
In this study, as shown in Table 36, treated subjects reported a mean increase of 2.1 days and a median
increase of 1 day from cycle length reported at screening. 82.5 of women had cycle length changes of
7 days or less. In the levonorgestrel arm, cycle was shortened by a mean of 1.2 days and a median of 1
day from cycle length reported at screening
Table 36 Duration of treatment cycle in ITT population of Study 513
UPA LNG
(N = 1,104) (N = 1,117)
- mean (sd) 30.8 (8.3) 27.5 (8.0)
- median 30.0 28.0
- range 9.0 to 93.0 8.0 to 68.0
- mean (sd) 2.1 (8.2) -1.2 (7.9)
- median 1.0 -1.0
- range -21.0 to 67.0 -22.0 to 40.0
7 days 82.5 90.0
>7 days 17.5 10.0
> 20 days 2.7 1.2
One ovarian cyst was observed in each treatment arm of the study: the one in the levonorgestrel
treatment arm ruptured and was reported as a SAE and the one in the ulipristal acetate treatment arm
ruptured and resulted in study withdrawal.

May 2010 Page 77 of 108
UPA LNG
N of pregnancies () Pregnancy outcome N of pregnancies () Pregnancy outcome
20 (2) - 15 induced terminations 30 (2) - 21 induced terminations
- 5 spontaneous miscarriages - 5 spontaneous miscarriages*
- 3 normal live births
* Including one biochemical pregnancy ** Lost to follow-up after pregnancy diagnosis
6.3.3 Pooled safety analyses
Demographics of the pooled Phase 3 safety population are presented in Appendix 7.
Overall, 1,473 (55.9%) of the 2,637 subjects in the pooled population reported a total of 3,738 AEs, of
which 1,781 (47.6%) were considered by the investigator as at least possibly related to the study
medication and 530 (14.2%) were of unknown or unspecified relationship.
Table 38 shows the incidence of AEs in 1% of the ITT pooled Phase 3 population independent of
causal relationship with study drugs.
Overall, the AEs reported during the Phase 3 studies were in their vast majority qualified as mild to
moderate. They disappeared in all cases within a few days following treatment. None of the AEs
appeared linked to the pharmacological properties of the molecule. None appeared to flag a potential,
unreported, serious effect.

May 2010 Page 78 of 108
Table 38 Incidence of Adverse Events in 1% of ITT pooled Phase 3 population subjects reported between
inclusion and end of the study (approximately one month)
Number of subjects (%) 2,637 (100)

At least one AE, n (%) 1,473 (55.9)
At least one SAE, n (%) 251 (9.5)
Headache 482 (18.3)
Nausea 328 (12.4)
Dysmenorrhea 244 (9.3)
Abdominal pain 236 (9.0)
Fatigue 147 (5.6)
Dizziness 140 (5.3)
Abdominal pain upper 86 (3.3)
Nasopharyngitis 72 (2.7)
Back pain 72 (2.7)
Pelvic pain 59 (2.2)
Abdominal distension 49 (1.9)
Vomiting 45 (1.7)
Vaginal discharge 40 (1.5)
Breast tenderness 36 (1.4)
Diarrheoa 34 (1.3)
Migraine 32 (1.2)
Muscle spasm 31 (1.2)
Somnolence 28 (1.1)
As shown in Table 39, treated subjects (ITT population who did not become pregnant after treatment
and received the study drug only once, n=2,488) reported a mean increase of 2.5 days and a median
increase of 1 day from cycle length reported at screening. The majority of women reported a change in
menstrual length of 7 days or less compared to usual cycle length.
Table 39 Duration of treatment cycle in subjects who did not become pregnant, in the ITT pooled Phase 3
population (first participation only)
N = 2,488
- mean (sd) 31.4 (9.5)
- median 30.0
- range 8.0 to 109.0
- mean (sd) 2.5 (9.4)
- median 1.0
- range -22.0 to 79.0
< -7 days 6.8
-7 days to -1 day 29.9
0 to +7 days 44.7
> +7 days 18.5

May 2010 Page 79 of 108
Menses following ulipristal acetate intake were normal in duration and volume in the majority of the
women. Only 8.7% (229/2,637) of subjects reported inter-menstrual bleeding after ulipristal acetate
intake, and in the vast majority of the cases (88.2%), this bleeding was described as spotting. Heavy
intermenstrual bleeding was reported in only 0.4% (11/2,637) subjects.
Subgroup safety analyses were performed to assess the effects of age, geographical region (Europe or
USA), BMI and race; they did not identify any specific issue in any of the subgroups studied (see
Appendix 8). The incidence of AE was lower in women >35 years old compared to the other age
groups, but the type and frequency of the most common AEs did not otherwise differ according to age
category. The type and frequency of AE did not differ between geographic regions, BMI category or
race.
6.4 Safety profile from repeated dose exposure
6.4.1 Repeated dose Study 510
In this study, healthy cycling women volunteers received daily oral doses of 2.5-, 5- or 10-mg
ulipristal acetate or matching placebo for 12 weeks.
Three SAEs were reported; one woman was diagnosed with Graves disease four weeks after the end
of treatment with 5-mg ulipristal acetate, but TSH and thyroid antibodies were already abnormal at
baseline. The second woman experienced acute abdominal pain and fever requiring hospitalization.
Exploratory tests showed only mild resolutive inflammatory syndrome. The event was considered
unlikely to be related to the study drug. A third woman had a preexisting dermoid ovarian cyst which
was removed two years after stopping the study treatment.
Overall, 41 (89%) subjects experienced at least one AE. The most frequently reported AE was
headache in all treatment groups.
In this study, post-treatment cycle characteristics were similar in the four arms, and there was no
significant difference from baseline except for progesterone level which indicated anovulatory cycles
in 50% of the samples from all groups, including placebo.
A total of 21 ovarian cysts were reported in 18 subjects in all four groups (2.5, 5 and 10 mg daily and
the placebo groups) during the treatment phase. All spontaneously resolved after the end of the
treatment except for the one described above as SAE in the 5-mg group which subsequently led to
ovariectomy nearly two years after stopping the study treatment. The pathology report showed
multiple functional cysts and one calcified benign cystadenoma. No ovarian cyst led to study
discontinuation.
Liver function tests showed no variation between baseline and after 3 months of treatment at 2.5-, 5- or
10-mg ulipristal acetate daily. No increase in ACTH and/or cortisol was observed. Prolactin,
testosterone and TSH levels also remained normal.

May 2010 Page 80 of 108
Endometrial biopsy was performed after approximately 10 weeks of treatment. Histological analysis is
presented in Table 40. No endometrial samples displayed hyperplasia or any atypia.
Table 40 Endometrial histology following 10 weeks of daily ulipristal acetate, in Study 510
Normal Mixed secretory Inactive with

Proliferative Atrophic No tissue
Secretory / proliferative cystic changes
Placebo
6 2 0 0 0 3
(n=11)
2.5-mg UPA
3 3 0 1 1 3
(n=11)
5-mg UPA
2 0 1 0 7 0
(n=11*)
10-mg UPA
0 0 2 2 1 4
(n=10*)
* 1 other: menstrual
6.4.2 Multiple enrollments in efficacy emergency contraception trials repeat use
Repeat enrollments in efficacy trials occurred in 88 women (4 in the Phase 2/3 trials and 84 in Phase
3). In the Phase 3 studies, subjects were allowed to enrol on multiple occasions provided that the
previous study participation was complete before re-enrollment. These subjects were analyzed in the
ITT population and also as a separate population: there were 84 / 2637 (3.2%) subjects who enrolled in
the studies more than once; 75 enrolled twice (including two subjects who enrolled in both Phase 3
studies) and 9 enrolled three times. There were no differences in the repeat enrollers in terms of
incidence or severity of AEs, menstrual cycle length, duration or volume of menstrual bleeding, or
inter-menstrual bleeding after ulipristal acetate.
6.5 Drug interactions
No drug-drug interactions associated with safety problems were observed during the clinical
development program. The potential interactions that have been identified are discussed here.
Ulipristal acetate is metabolized by CYP3A4 enzyme in human liver microsomes in vitro (Study 430).
Therefore, co-administration with potent CYP3A4 inhibitors could increase exposure to ulipristal
acetate. Co-administration with potent CYP3A4 inducers could reduce plasma concentration of
ulipristal acetate and result in a decrease in efficacy.
6.6 Post-marketing safety experience
ellaOne (ulipristal acetate 30-mg tablet, identical to the tablet subject to the present application) is
currently approved in 30 countries (European Union, Norway, Iceland and Lichtenstein). The first
marketing authorization was granted by centralized procedure on 15 May 2009 for EC within 120
hours (5 days) of unprotected sexual intercourse or contraceptive failure. As of May 12, 2010, ellaOne
was marketed in 20 countries. From the product safety information collected and assessed by HRA
Pharma pharmacovigilance department, one Serious Adverse Event was reported. No particular safety

May 2010 Page 81 of 108
signal was detected. Eighteen pregnancies have been reported, of which eleven were ongoing, two had
been electively terminated and one ended in a spontaneous miscarriage at the time of report.
6.7 Pregnancy
collected by in clinical trials reported in this NDA (n=92) or via post-marketing surveillance (n=18);
one additional pregnancy was recently reported in an ongoing repeat-dose pharmacokinetic trial
conducted by another sponsor and is described here.
For the 92 pregnancies from HRA Pharma clinical trials, outcome information is as follows: 61
induced terminations, 14 spontaneous miscarriages and 6 normal live births (Table 41). One of the
delivered babies presented with optic nerve hypoplasia diagnosed at 2 months of age, which was not
considered secondary to treatment intake by investigators, and for which no etiology has been
identified by the treating physicians during work-up. Eleven women who became pregnant were lost to
follow-up. Ten of the pregnancies diagnosed in clinical trials were subsequently found to have begun
prior to ulipristal acetate intake.
A case of pregnancy was reported during a multiple dose pharmacokinetics trial conducted in healthy
female subjects by another sponsor. A 31 year-old female subject participating to the trial was
screened on 13 January 2010, and at that time, the urinary pregnancy test (beta-HCG) was found to be
negative. Subsequently, the subject was randomized and took 20-mg ulipristal acetate daily between 3
February 2010 and 12 February 2010. A pregnancy was discovered on 23 February 2010 (end of study
visit). A pelvic ultrasound was then performed showing a diamniotic gemellary pregnancy with an
estimated gestational age of 7/8 weeks for one of the sacs (pregnancy beginning on 18 January 2010
5 days). The vitality of the other sac was uncertain. On the same day, the blood beta-HCG was found
to be increased up to 146,150 U/L. Subsequently, blood samples collected on 19 January 2010
(screening) and on 3 February 2010 (randomization) were retrospectively analyzed and found beta-
HCG to be negative and increased to 107 U/L, respectively. The reported the expected delivery date is
18 October 2010.

May 2010 Page 82 of 108
Table 41 Pregnancies and outcome, in clinical development program for EC
Study UPA LNG

(n subjects in
N of pregnancies () Pregnancy outcome N of Pregnancy outcome
UPA treatment
arms) pregnancies ()
(Dose) (Dose)
Phase 1: 503 1 - 1 normal live birth
(n= 31) (200-mg unmicronized)
Phase 1: 506 1 - 1 normal live birth
(n=56) (10-mg unmicronized)
Phase 2/3: 12 (4) - 9 induced terminations 14 (1) - 8 induced terminations
507 (50-mg unmicronized) - 1 spontaneous miscarriage (0.75-mg 2) - 5 spontaneous miscarriages*
(n= 832) - 2 lost to follow up** - 1 normal live birth
Phase 2/3: 11 (1) 10-mg micronized:
508 (10-mg micronized) - 9 induced terminations
(n=1,026) - 1 normal live birth
5 (0) 50-mg unmicronized:
(50-mg unmicronized) - 4 induced terminations
13 (2) 10-mg unmicronized:
(10-mg unmicronized) - 8 induced terminations
- 3 lost to follow up**
Phase 3: 509 29 (1) - 16 induced terminations
(n= 1,533) (30-mg micronized) - 6 spontaneous miscarriages
- 1 delivery of a baby with
subsequent diagnosis of
severely altered vision***
Phase 3: 513 20 (2) - 15 induced terminations 30 (2) - 21 induced terminations
(n= 1,104) (30-mg micronized) - 5 spontaneous miscarriages (1.5-mg) - 5 spontaneous miscarriages*
* Including one biochemical pregnancy ** Lost to follow-up after pregnancy diagnosis *** Assessed as unrelated to UPA
exposure
For the 18 pregnancies from post-marketing surveillance, the most recent follow-up information is
presented (Table 42): eleven were ongoing, two had been electively terminated and one ended in a
spontaneous miscarriage at the time of report.

May 2010 Page 83 of 108
Table 42 Pregnancies and outcome in post-marketing surveillance of ellaOne
Country Notification date Pregnancy outcome as of May 12, 2010

France 26 Nov 2009 Unknown (refusal from physician to give information)
Belgium 19 Nov 2009 Unknown (lost to follow-up)
Germany 25 Jan 2010 Ongoing uneventful pregnancy (20th week)
France 27 Jan 2010 Ongoing uneventful pregnancy
France 11 Feb 2010 Unknown (refusal from patient to give information)
UK 03 Feb 2010 Ongoing uneventful pregnancy
UK 25 Feb 2010 Ongoing uneventful pregnancy
France 09 Mar 2010 Ongoing uneventful pregnancy
UK 02 Apr 2010 Ongoing uneventful pregnancy
UK 06 Apr 2010 Ongoing uneventful pregnancy
UK 15 Apr 2010 Spontaneous miscarriage
Spain 20 Apr 2010 Unknown (lost to follow-up)
France 22 Apr 2010 Elective termination of pregnancy
Germany 22 Apr 2010 Ongoing uneventful pregnancy
France 23 Apr 2010 Elective termination of pregnancy
France 21 Apr 2010 Ongoing uneventful pregnancy
Germany 12 May 2010 Ongoing uneventful pregnancy
Spain 12 May 2010 Ongoing uneventful pregnancy
6.8 Safety conclusions
The clinical development program, conducted in a broad population demographically representative of

the population of US women who are candidates for EC did not bring to light specific risks associated
with ulipristal acetate, even after repeat dose exposure. The most common adverse events were
headache, nausea, dysmenorrheal and abdominal pain, a profile similar to that reported in the parallel
levonorgestrel groups in randomized trials.
Exploration of the pituitary adrenal axis during Phase one studies did not show hormonal
modifications which suggest clinical cortisol blockade. Information on drug interaction is limited, but
given the treatment regimen in emergency contraception (single dose administration), possible
interactions should have little clinical relevance. The safety of ulipristal acetate has not been evaluated
in patients with hepatic or renal impairment.
As for any new drug, accidental exposure during pregnancy has unknown consequences, since data on
newborns from mothers exposed to the compound during pregnancy is limited. No studies have been
performed on the use of ulipristal acetate in pregnant women, but available data on inadvertent
exposure of very early pregnancy to ulipristal acetate in clinical trials (section 6.7) at the to-be-
marketed dose for EC indicate that the product does not interrupt an established pregnancy.
Nevertheless, would pregnant women be exposed to ulipristal acetate, the theoretical effects on the
course of pregnancy itself and on the fetus are the following:

May 2010 Page 84 of 108
- Miscarriage: in the clinical development program as indicated in section 6.7, two randomized studies
compared ulipristal acetate and levonorgestrel; the proportion of pregnancies detected in the trials that
ended in miscarriage was not different in the two EC treatments.
- Ectopic pregnancy: in clinical studies no ectopic pregnancies have been observed, but the number of
pregnancies is too low to allow any definitive conclusion. In contrast to progestins, progesterone
receptor modulators do not appear to have an effect on tubular motility (Gazvani et al, 1998; Gemzell
et al, 2004). There is therefore no reason to anticipate an increased risk of ectopic pregnancy in the
event of ulipristal acetate failure for EC.
- Fetal abnormalities, congenital malformations and offspring fertility, possible effects on the fetus: in
animals in which ulipristal acetate did not prevent pregnancy maintenance, the fetuses developed
normally. Furthermore, the F1 generation of pups from rats treated in the early days after mating
developed normally. In a peri-post natal study in which animals were exposed from day 6 of gestation
through to weaning of the F1 offspring, no subsequent adverse effect of maternal treatment on pre- or
post-natal development of the F1 offspring was observed, including their reproductive performance.
Use of ulipristal acetate in nursing women constitutes another area where there are no human data.
Many hormones with similar chemical structure are excreted in breast milk, and data from animal
studies indicate that ulipristal acetate is present in milk in lactating female rats. Lactating women were
systematically excluded from clinical trials, thus no efficacy data are available in this population.
Therefore, no specific data on ulipristal acetate transfer into human milk is available and as many
drugs are excreted in human milk, caution should be exercised when the product is administered to a
nursing woman.
HRA Pharmas US partner for distribution of the product (Watson Pharmaceuticals, Inc) has
comprehensive pharmacovigilance and medical information capacities that will be employed to ensure
appropriate training on appropriate drug use and monitoring of drug safety.

May 2010 Page 85 of 108
7 BENEFIT/RISK ASSESSMENT & CONCLUSIONS
There is a medical need for an efficient emergency contraceptive product which acts consistently over
a prolonged time period. The evidence presented in this NDA demonstrates that ulipristal acetate
would offer the following benefits as an intervention for EC:
- Consistent efficacy: In a series of four efficacy trials in which over 4,000 women seeking a
contraceptive intervention at a family planning clinic after unprotected intercourse or a
contraceptive failure received ulipristal acetate, ulipristal acetate consistently and significantly
reduced pregnancy risk, from an expected rate of approximately 5.5% to an observed
pregnancy rate less than 2%. Ulipristal acetate prevents pregnancy.
- Enhanced inhibition of ovulation: Pharmacodynamic data demonstrate that ulipristal acetate

potently delays ovulation for five or more days when given in the follicular phase, even in the
hours leading up ovulation when intercourse is at highest risk of leading to pregnancy.
Currently-marketed products appear to delay ovulation only if administered several days
beforehand.
- More time: Data collected in efficacy trials on women enrolled up to 120 h after unprotected
intercourse demonstrate that ulipristal acetate consistently reduced pregnancy risk over the
entire five-day window. In comparison to marketed products which are labeled for use up to
72 h, ulipristal acetate would offer two additional days for EC intervention.
No specific safety signals or potential risks have been identified in an extensive nonclinical and
clinical development program encompassing studies at higher doses and for longer duration than the
30-mg dose proposed for marketing for EC. The adverse events reported in the EC trials were similar
in frequency and severity to those observed in parallel levonorgestrel comparator groups, with
headache, nausea, dysmenorrheal and abdominal pain the most commonly reported.
However, ulipristal acetate is a new chemical entity and compared to levonorgestrel, experience with
this new entity is limited. The results of non clinical studies designed to assess potential reproductive
toxicity (including peri and postnatal exposure) are reassuring and pharmacovigilance will be carefully
monitored to gather information on actual use to reinforce the existing safety database.
Exploratory analyses conducted on the clinical database have confirmed the consistency of ulipristal
acetate efficacy across demographic groups (age, race) and detected certain risk factors for increased
risk of pregnancy. These findings are useful for constructive clinical recommendations to optimize
efficacy. Subsequent acts of intercourse in the same cycle after using ulipristal acetate for EC are at
risk of pregnancy, so it is important to recommend resumption or initiation of ongoing contraception in
women who continue to have unprotected intercourse. Pregnancy rates increased with high BMI (even
more markedly in levonorgestrel comparator groups than for ulipristal acetate), which underlines the
importance of contraceptive counseling for overweight and obese women (SFP Guidelines, 2009).

May 2010 Page 86 of 108
In light of the prevalence of unintended pregnancy in the US, there is a need for additional
contraceptive options. Recognizing that contraceptive mishaps and unexpected intercourse happen, a
highly-effective method of EC that consistently reduced pregnancy risk when used even up to several
days after intercourse could give women a true second chance to prevent an unplanned pregnancy. The
evidence presented here demonstrates that ulipristal acetate is safe and effective for EC and that its
benefits outweigh its risks. US women would stand to benefit from having ulipristal acetate available
as their second chance.

May 2010 Page 87 of 108
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9 APPENDICES

May 2010 Page 94 of 108
Appendix 1 List of clinical studies
Table 43: Tabular listing of all clinical studies
Type of Study Objective(s) of the Study Study Design Test Product(s): Dosage Number Healthy Subjects or Duration Study Status;
Study # and Type of Regimen; Route of of Diagnosis of of Type of Report
Control Administration Subjects Patients Treatment
PK 501 To compare the absorption Cross-over design UPA 10-mg 9 Healthy women Single dose Final study report
profile of three dosage unmicronized gelatin volunteers April 2006
forms (by LC-MS/MS) capsule
UPA 10-mg micronized
gelatin capsule
UPA 10-mg micronized
tablet
Oral
Bioequi 516 To compare the Randomised two- UPA 30-mg tablet 54 Healthy women Single dose Final study report
valence bioavailability of 30 mg- way cross-over, 2 Cardinal Health, France volunteers 16 September
tablets of UPA treatments, 2 UPA 30-mg tablet Lon 2009
manufactured at LEON periods, 2 Farma, Spain
Farma (Spain) with 30 mg- sequences, Oral
tablets of UPA open (blind for
manufactured at Cardinal the bioanalysis),
Health France (France) single dose study
PK/PD 503 To determine the PK-PD Prospective, UPA 1-, 10-, 50-, 100- or 37 Healthy Single dose Publication
profile of escalating doses randomized 200-mg unmicronized normally cycling Pasarro M.
with late luteal-phase placebo- gelatin capsule women volunteers Human
treatment (by RIA) controlled dose Placebo gelatin capsule Reproduction,
escalation Oral 2003
PK 504 To determine the PK profile Single treatment UPA 30-mg tablet 20 Healthy women Single dose Final study report
of a single dose in tablet Single center Oral volunteers 30 April 2008
PD 505 To determine the PD profile Prospective, UPA 10-, 50- or 100-mg 45 Healthy normally Single dose Publication
of different doses with mid- randomized unmicronized gelatin cycling women Stratton P.
follicular-phase treatment placebo- capsule volunteers Human
controlled Placebo gelatin capsule Reproduction,
Oral 2000
PD 506 To determine the PD profile Prospective, UPA 10-, 50- or 100-mg 71 Healthy normally Single dose Manuscript for
of different doses with early randomized unmicronized gelatin cycling women Publication
luteal phase treatment placebo- capsule volunteers Stratton P.
controlled Placebo gelatin capsule 2008
Oral

May 2010 Page 95 of 108
PD 510 To determine PD profile Prospective, UPA 2.5-, 5- or 10-mg 46 Healthy normally Daily for Final study report
with continuous randomized, micronized tablet cycling women 12 weeks 24 April 2008
administration over 3 double-blind, Placebo tablet volunteers
months multicenter, Oral
placebo-
controlled
PD 511 To compare the effect of a Double-blind, UPA 30-mg micronized 34 Healthy normally Single dose Final study report
single oral dose of CDB- randomized, tablet cycling women 28 July 2009
2914 and placebo on the cross-over, Placebo tablet 34 volunteers
outcome of the leading placebo- Oral
follicle and more controlled
specifically look for
inhibition of follicle rupture
PK 512 To evaluate the impact of Randomised two- UPA 30-mg tablet 18 Healthy subjects Single dose Final study report
concomitant food intake on way cross-over, p.o., administered in 28 October 2008
the relative bioavailability two treatments, fasted or fed conditions
of ulipristal acetate (30 mg, two periods, two
tablet) sequences, open
(blind for the
bioanalysis),
single dose study
Efficacy 507 To study the efficacy, safety Prospective, UPA 50-mg 832 Healthy women Single Dose Final study report
and and tolerance in comparison randomized unmicronized gelatin requesting 7 August 2006
Safety to levonorgestrel for double-blind, capsule emergency
emergency contraception multicenter, LNG 0.75-mg tablet contraception within
active-controlled Oral 72h after intercourse/
group
Efficacy 508 To study the efficacy, safety Prospective, UPA 50-mg 400 Healthy women Single dose Final study report
and and tolerance of two randomized unmicronized gelatin requesting 5 March 2004
Safety different doses for double-blind, capsule emergency
emergency contraception multicenter, UPA 10-mg micronized contraception within
active-controlled gelatin capsule 72h after
Oral intercourse/group
Efficacy 509 To study the efficacy, safety Prospective, open- UPA 30-mg micronized 1533 Women aged 18 year Single dose Final study report
and and tolerance of a single label, single arm, tablet treated of age or older 5 May 2008
Safety dose for emergency multicenter, Oral 1241 enrolled for
contraception mITT emergency
contraception

May 2010 Page 96 of 108
Efficacy 513 To demonstrate that the Prospective, UPA 30-mg micronized 1104 Women aged 16 year Single dose Final study report
and pregnancy rate observed single-blind, Tablet treated of age or older 5 June 2009
Safety after taking CDB-2914 (30 randomized, Oral 1013 enrolled for
mg) within 72h of multicenter, 2-arm mITT emergency
unprotected intercourse parallel contraception
(UPI) is statistically comparative study LNG 1.5 mg tablet 1117
significantly lower than the design Oral treated
estimated expected 1046
pregnancy rate in the mITT
absence of emergency
contraception (EC)

May 2010 Page 97 of 108
Appendix 2 Demographics of Phase 2/3 study populations

Table 44 Demographics of the Study 507 population
UPA LNG All subjects

Characteristic, n (%) (N=832) (N=840) (N=1672)
Age at Randomization (years)
18-19 160 (19) 177 (21) 337 (20)
20-24 348 (42) 355 (42) 703 (42)
25-29 186 (22) 171 (20) 357 (21)
30-34 83 (10) 83 (10) 166 (10)
35-39 34 (4) 38 (5) 72 (4)
40-44 14 (2) 14 (2) 28 (2)
45+ 7 (1) 2 (<1) 9 (1)
Mean, SD 24.4 5.77 24.2 5.59 24.3 5.68
Race
American Indian/Alaska Native 7 (1) 5 (1) 12 (1)
Asian 44 (5) 55 (7) 99 (6)
Black/African American 134 (16) 124 (15) 258 (15)
Native Hawaiian/Pacific Islander 3 (<1) 8 (1) 11 (1)
White 611 (73) 612 (73) 1223 (73)
Other 32 (4) 36 (4) 68 (4)
Ethnicity
Hispanic/Latino 123 (15) 147 (18) 270 (16)
Not Hispanic/Latino 709 (85) 692 (82) 1401 (84)
Marital Status
Single 739 (89) 729 (87) 1468 (88)
Married 37 (4) 43 (5) 80 (5)
Separated 22 (3) 26 (3) 48 (3)
Divorced 34 (4) 41 (5) 75 (4)
Widowed 0 (0) 1 (<1) 1 (<1)
Living Arrangement
Living with partner 138 (17) 132 (16) 270 (16)
Not living with partner 691 (83) 706 (84) 1397 (84)
Education Level
Less than 12 years 30 (4) 44 (5) 74 (4)
High school graduate 79 (9) 100 (12) 179 (11)
Some college 448 (54) 427 (51) 875 (52)
College graduate 226 (27) 223 (27) 449 (27)
Masters or Doctorate level 49 (6) 45 (5) 94 (6)
Smoking Status
Current smoker 273 (33) 308 (37) 581 (35)
Less than one pack per day 242 (29) 269 (32) 511 (31)
One or more packs per day 31 (4) 39 (5) 70 (4)
Former smoker 127 (15) 122 (15) 249 (15)
Never smoked 432 (52) 410 (49) 842 (50)
Frequency of Alcohol Intake
Never 111 (13) 118 (14) 229 (14)
Less than once per month 122 (15) 133 (16) 255 (15)
At least once per month 248 (30) 216 (26) 464 (28)
At least once per week 333 (40) 352 (42) 685 (41)
At least once per day 17 (2) 20 (2) 37 (2)

May 2010 Page 98 of 108
Table 45 Demographics of the Study 508 population
UPA 10-mg micronized UPA 50-mg All subjects

Age at Randomization (years)
18-19 74 (19) 94 (23) 168 (21)
20-24 176 (44) 157 (38) 333 (41)
25-29 83 (21) 92 (22) 175 (22)
30-34 35 (9) 49 (12) 84 (10)
35-39 23 (6) 11 (3) 34 (4)
40-44 8 (2) 8 (2) 16 (2)
45+ 0 (0) 2 (<1) 2 (<1)
Mean, SD 24.4 5.56 24.4 5.55 24.4 5.55
Race
Asian 28 (7) 18 (4) 46 (6)
Black or African American 79 (20) 66 (16) 145 (18)
Native American or Alaskan 5 (1) 6 (1) 11 (1)
Native Hawaiian/Pacific Islander 2 (1) 4 (1) 6 (1)
White 264 (66) 300 (73) 564 (69)
Other 21 (5) 18 (4) 39 (5)
Ethnicity
Hispanic or Latino 72 (18) 75 (18) 147 (18)
Neither Hispanic nor Latino 326 (82) 338 (82) 664 (82)
Marital Status
Never Married 357 (89) 364 (88) 721 (89)
Married 14 (4) 15 (4) 29 (4)
Separated 7 (2) 14 (3) 21 (3)
Divorced 18 (5) 20 (5) 38 (5)
Widowed 3 (1) 0 (0) 3 (<1)
Living Arrangement
Living with partner 68 (17) 66 (16) 134 (17)
Not living with partner 330 (83) 347 (84) 677 (83)
Education Level
Less than 12 years 16 (4) 11 (3) 27 (3)
High school graduate 51 (13) 46 (11) 97 (12)
Some college 221 (55) 223 (54) 444 (55)
College graduate 91 (23) 103 (25) 194 (24)
Masters or Doctorate level 20 (5) 30 (7) 50 (6)
Alcohol Intake
Never 53 (13) 41 (10) 94 (12)
Less than once per month 74 (19) 83 (20) 157 (19)
At least once per month 115 (29) 122 (30) 237 (29)
At least once per week 152 (38) 159 (38) 311 (38)
At least once per day 5 (1) 8 (2) 13 (2)
Smoking Status
Current smoker 136 (34) 144 (35) 280 (34)
Former smoker 80 (20) 72 (17) 152 (19)
Never smoked 183 (46) 197 (48) 380 (47)

May 2010 DRAFT Page 99 of 108
UPA 10-mg micronized UPA 50-mg All subjects

Height (in)
n 399 413 812
Mean 65.1 64.7 64.9
SD 2.95 2.90 2.93
Median 65.0 65.0 65.0
Min, Max 55,74 54,73 54,74
Weight (lbs)
n 398 413 811
Mean 147.2 147.5 147.4
SD 37.23 33.45 35.33
Median 138.0 140.0 139.0
Min, Max 82,371 97,300 82,371

Appendix 3 Efficacy subgroup analyses

Table 46 Pregnancy rates observed and expected after ulipristal acetate treatment according to intrinsic factors
(pooled Phase 3 population)
Number of subjects Observed PR, % Expected PR, %

(95% CI)
Age
<18 34 0 6.74%
18-25 1515 2.31% 5.59%
(1.66-3.21)
> 25-35 637 1.88% 5.66%
(1.04-3.30)
>35 159 1.26% 6.51%
(0.05-4.76)
P* P=0.853
Region
Europe 300 1.33% 6.21%
(0.39-3.50)
US 1880 1.97% 5.53%
(1.42-2.71)
P* P=0.646
Race
White 1450 2.0% 5.78%
(1.39-2.87)
Black or African American 432 2.31% 5.05%
(1.20-4.27)
Asian 41 2.44% 5.32%
(-0.71-13.74)
Other 253 0.40% 5.83%
(-0.16-2.43)
P* P=0.191
BMI
< 25 1322 1.66% 5.72%
(1.09-2.52)
25-27 253 0.79% 5.61%
(0.03-3.03)
>27-30 252 2.38% 6.68%
(0.97-5.22)
> 30 351 3.13% 4.55%
(1.69-5.59)
P* P=0.146
Pregnancy history
Yes 1029 2.43% 5.87%
(1.63-3.58)
No 1151 1.39% 5.40%
(0.84-2.26)
P* P=0.464
*Comparison among the groups, Fishers exact test

Table 47 Pregnancy rates observed and expected after ulipristal acetate treatment for each subgroup population
and extrinsic factor (pooled Phase 3 population)
N of subjects Observed PR, % Expected PR, %

(95% CI)
Repeat use of ulipristal
First intake 2352 2.08% 5.67%
(1.57-2.75)
Subsequent intake in the same cycle 4 0 0
Subsequent intake in a different cycle 89 0 5.13%
P* P= 0.464
Further unprotected intercourse
No 2050 1.61% 5.62%
(1.14-2.26)
Yes 130 6.15% 5.67%
(2.97-11.85)
P* P=0.002
Food intake**
Less than 2 h before treatment intake 279 1.79% 5.27%
(0.65-4.25)
2 h or more before treatment intake 905 1.44% 5.56%
(0.82-2.47)
P* P=0.779
*Comparison among the groups, Fishers exact test ** Data collected in a subset of subjects (N=1,185)

Appendix 4 Single dose safety exposure
Table 48 Number of subjects exposed to ulipristal acetate (single dose administration) during clinical studies in EC
Study Phase Ulipristal acetate dose Subjects evaluated for safety

501 1 Two way cross over: 10
- 10-mg unmicronized, capsule
- 10-mg micronized capsule
- 10-mg micronized tablet
503 1 - 1-mg 6
- 10-mg 6
- 50-mg 6
- 100-mg 7
- 200-mg 6
(unmicronized formulations)
504 1 30-mg micronized tablet 20
505 1 - 10-mg 11
- 50-mg 11
- 100-mg 10
506 1 - 10-mg 13
- 50-mg 14
- 100-mg 14
511* 1 30-mg micronized tablet 35
507 2/3 50-mg unmicronized capsule 832
508 2/3 - 10-mg micronized capsule 399
- 10-mg unmicronized capsule 214
- 50-mg unmicronized capsule 413
* Study performed with the to-be-marketed 30-mg tablet

Appendix 5 Safety results from Phase 1 studies (single dose administration)
Table 49 Adverse Event frequencies and most common Adverse Events in Phase 1 studies, single administration
Study # (n of subjects in AEs Most common AEs

UPA arms) n of AEs % of subjects
501 (10) 8 60 Headache
503 (31) 2 5.5 1 skin rash, 1 hot flush
504 (20) 6 15 Nausea, headache
505 (32) 6 16 Gastrointestinal disorders, headache
506 (41) 0 0 -
511 (35) 65 39.6 Headache, dysmenorrhea, lower abdominal pain
512 (19) 28 68.4 Nausea, abdominal pain, headache
516 (53) 7 9.4 Nausea, vomiting
Table 50 Summary of laboratory tests findings in Phase 1 studies, single administration
Study # Evaluated parameters Findings

503, 505, 506 Post treatment standard lab tests Normal values
504 Pre and post treatment standard lab 15 subjects had at least one out-of-range value.
tests Most frequent abnormalities:
- low eosinophils (6 subjects)
- low haematocrit (6 subjects)
- low haemoglobin (5 subjects)
- low red blood cell count (3 subjects).
No abnormality deemed clinically important by the investigator.
511 and 512 Pre and post treatment standard lab No clinically significant abnormal laboratory values were
tests observed at the end-of-study visit
516 Pre and post treatment standard lab 3 subjects with clinically relevant changes:
tests - low neutrophil count before the second period leading to study
withdrawal (1 subject)
- low neutrophil count at the beginning of period 2 resolved at the
end of the study (1subject)
- low haemoglobin level at the beginning of period 2 leading to
study withdrawal (1 subject)

Appendix 6 Safety results from Phase 2/3 studies (507, 508)
Table 51 Incidence of Adverse Events in 1% of ITT population subjects, in Study 507
UPA 50-mg LNG 0.75-mg2

(N = 832) (N = 840)
At least one AE, n (%) 639 (77.0) 636 (76.0)
At least one SAE, n (%) 2 (0.2) 0
Fatigue 312 (37.5) 300 (36.0)
Headache 269 (32.3) 274 (33.0)
Nausea 256 (30.8) 221 (26.0)
Dizziness 165 (19.8) 147 (18.0)
Pelvic / ovarian / uterine pain 160 (19.2) 167 (19.9)
Breast tenderness 135 (16.2) 140 (17.0)
Diarrhea 105 (12.6) 101 (12.0)
Dysmenorrhea 68 (8.2) 59 (7.0)
Abdominal pain lower 63 (7.6) 65 (8.0)
Abdominal pain 28 (3.3) 19 (2.0)
Vomiting 29 (3.5) 19 (2.0)
Nasopharyngitis 27 (3.2) 37 (4.4)
Bladder infection 24 (2.9) 7 (1.0)
Myalgia 13 (1.6) 8 (1.0)
Flu / pyrexia 11 (1.3) 6 (1.0)
Back pain 9 (1.1) 9 (1.0)
Pharyngolaryngeal pain 9 (1.1) 7 (1.0)
Mood swings 8 (1.0) 0
Metrorragia 7 (0.8) 10 (1.0)
Vaginal candidiasis / vaginitis 7 (0.8) 12 (1.4)

Table 52 Incidence of Adverse Events in 1% of ITT population subjects, in Study 508
UPA 10-mg* UPA 10-mg UPA 50-mg*

(N = 214) (N = 399) (N = 413)
At least one AE, n (%) 157 (73.4) 315 (78.9) 314 (76)
At least one SAE, n (%) 0 0 0
Pelvic / ovarian / uterine pain 70 (32.7) 135 (33.8) 138 (33.4)
Headache 54 (25.0) 120 (30.0) 121 (29.3)
Fatigue 56 (26.0) 102 (26.0) 101 (24.5)
Nausea 60 (28.0) 132 (33.0) 99 (24.0)
Dizziness 30 (14.0) 65 (16.0) 57 (13.8)
Breast tenderness 27 (13.0) 53 (13.0) 49 (11.9)
Irregular menstruation 33 (15.0) 50 (13.0) 47 (11.4)
Diarrhea 15 (7.0) 48 (12.0) 40 (9.7)
Abdominal pain 23 (10.8) 46 (12.0) 39 (9.4)
Metrorragia 9 (4.0) 26 (7.0) 22 (5.3)
Dysmenorrhea 4 (2.0) 6 (2.0) 11 (2.7)
Vomiting 11 (5.0) 16 (4.0) 12 (2.9)
Nasopharyngitis 5 (2.0) 11 (3.0) 12 (2.9)
Back pain 4 (2.0) 15 (4.0) 11 (2.7)
Vaginal candidiasis / vaginitis 17 (4.3) 9 (2.2)
Flu / pyrexia 5 (1.0) 4 (1.0)
Pharyngolaryngeal pain 4 (1.0)
Mood swings 4 (1.0) 4 (1.0)
Myalgia 3 (1.0) 5 (1.0)
Insomnia 5 (1.0)
Depression 5 (1.0)
Acne 5 (1.0)
* unmicronized

Appendix 7 Demographics of the pooled Phase 3 safety population
Table 53 Demographics of the pooled Phase 3 safety population
UPA 30-mg
Characteristics (N = 2537)
Age (years)
- Mean SD 24.5 6.1
- Range 16-52
- 16-17 41 (1.6%)
- 18 - 20 713 (28.1%)
- 21 25 940 (37.1%)
- 26 30 460 (18.1%)
- 31 35 217 (8.6%)
- 36 166 (6.5%)
Race, n (%)
- White 1684 (66.5%)
- Black or African American 498 (19.7%)
- Asian 47 (1.9%)
- American Indian or Alaska native 20 (0.8%)
- Native Hawaiian or other Pacific Islander 14 (0.6%)
- Other 269 (10.6%)
Height (cm)
- Mean SD 164.3 7.3
Weight (kg)
- Mean SD 68.4 17.0
- Mean SD 25.3 6.1

Appendix 8 - Subgroup safety analyses
according to age, geographical region and BMI
Age Geographical BMI

region
<18 18-25 >25-35 > 35 US Europe <25 25-27 >27-30 >30
Number of 44 1722 700 171 374 2263 1570 308 314 440
subjects
Nausea 9.1 9.3 10.1 5.3 9.6 9.2 8.2 12.0 9.2 11.4
Headache 6.8 9.2 9.1 6.4 8.6 9.0 8.5 8.8 9.9 10.0
Dysmenorrhea 2.3 5.3 6.3 1.7 6.7 5.1 5.0 6.2 6.7 4.5
Abdominal pain NR 5.3 6.1 1.7 4.3 5.4 4.8 6.5 6.7 4.8
(unspecified)
Fatigue NR 3.7 3.6 1.2 4.3 3.4 3.9 2.6 3.5 2.5
Dizziness NR 3.4 3.6 1.7 2.3 3.4 3.2 1.6 4.5 4.1
Upper NR 2.0 2.3 1.7 2.1 2.0 2.0 2.0 2.9 1.4
abdominal pain
Pelvic pain NR 1.0 2.1 1.2 0.3 1.5 1.2 1.3 0.6 2.3
Back pain NR 1.1 1.1 1.2 1.1 1.1 0.8 1.3 1.3 1.9
Vomiting NR 1.2 0.9 NR 1.1 1.0 0.8 1.3 1.3 1.1
Table 55 Incidence (in %) of Adverse Events in 1% of pooled Phase 3 safety population subjects according to race
White Black / African Asian Others

American
(N = 1,725) (N = 538) (N = 48) (N = 321)
Nausea 9.9 7.8 8.3 9.0
Headache 8.4 11.0 8.3 8.7
Dysmenorrhea 5.5 5.0 4.2 5.0
Abdominal pain (unspecified) 6.4 3.0 NR 3.7
Fatigue 4.1 2.6 4.2 1.6
Dizziness 3.4 4.1 2.1 1.9
Upper abdominal pain 2.2 1.7 NR 1.9
Pelvic pain 1.6 1.1 2.1 NR
Back pain 1.1 0.9 2.1 1.2
Vomiting 1.0 1.3 NR 0.3


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Advisory Committee for Reproductive Health Drugs

Ulipristal acetate 30 mg tablet

June 17, 2010 Briefing Materials

AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION

3.2 Unintended pregnancy: a public health challenge ................................................................... 20

3.2.1 Contraception practice...................................................................................................... 20

3.2.2 High rates of unintended pregnancies .............................................................................. 21

3.2.3 Contraceptive discontinuation .......................................................................................... 22

3.2.4 Contraceptive failures ...................................................................................................... 22

3.2.5 Estimating the need for emergency contraception ........................................................... 23

3.3 History of emergency contraception and available methods ................................................... 24

3.4 Need for additional treatment options ..................................................................................... 25

4 ULIPRISTAL ACETATE PRODUCT RATIONALE ............................................................28

4.2 Product background ................................................................................................................. 28

4.3 Overview of development program ......................................................................................... 30

4.3.1 Nonclinical studies ........................................................................................................... 30

4.3.2 Clinical studies ................................................................................................................. 30

4.4 Regulatory history ................................................................................................................... 31

4.4.1 Interactions with FDA ...................................................................................................... 31

4.4.2 Foreign approvals ............................................................................................................. 33

4.5 Preclinical overview ................................................................................................................ 33

4.5.1 Primary Pharmacology ..................................................................................................... 33

4.5.2 Safety pharmacology ........................................................................................................ 37

AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION

4.5.3 Pharmacokinetics ............................................................................................................. 37

4.5.4 Toxicology ....................................................................................................................... 38

4.6 Clinical Pharmacology & Mechanism of Action .................................................................... 41

4.7 Rationale for dose determination ............................................................................................. 45

4.8 Overview of efficacy trials ...................................................................................................... 45

4.8.1 Methods of efficacy trials ................................................................................................. 46

4.8.2 Rationale for the choice of clinical thresholds ................................................................. 49

4.8.3 Methods of pooled efficacy analysis ................................................................................ 49

5 CLINICAL EFFICACY ................................................................................................................51

5.2.1 Study 507.......................................................................................................................... 51

5.2.2 Study 508.......................................................................................................................... 52

5.3 Disposition and demographics in Phase 3 studies ................................................................... 54

5.4 Primary efficacy results ........................................................................................................... 58

5.5 Additional efficacy analyses .................................................................................................... 59

5.5.1 Efficacy over time ............................................................................................................ 59

5.5.2 Comparative efficacy vs. levonorgestrel .......................................................................... 60

5.6 Generalizability of efficacy data.............................................................................................. 63

6 CLINICAL SAFETY .....................................................................................................................65

6.2 Exposure to ulipristal acetate ................................................................................................... 65

6.2.1 Sources of information and overall extent of exposure.................................................... 65

6.2.2 Collection and analysis of safety data .............................................................................. 67

AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION

6.3 Safety from single dose exposure ............................................................................................ 69

6.3.1 Serious adverse events ..................................................................................................... 69

6.3.2 Individual study results .................................................................................................... 71

6.3.3 Pooled safety analyses ...................................................................................................... 78

6.4 Safety profile from repeated dose exposure ............................................................................ 80

6.4.1 Repeated dose Study 510 ................................................................................................. 80

6.5 Drug interactions ..................................................................................................................... 81

6.6 Post-marketing safety experience ............................................................................................ 81

6.7 Pregnancy ................................................................................................................................ 82

6.8 Safety conclusions ................................................................................................................... 84

7 BENEFIT/RISK ASSESSMENT & CONCLUSIONS ...............................................................86

Table 5 In vivo hormonal activity of ulipristal acetate (Study 404) ....................................................... 35

Table 7 Post-coital activity of ulipristal acetate in rats and rabbits ....................................................... 36

Table 8 Safety pharmacology profile of ulipristal acetate ..................................................................... 37

AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION

Table 9 Repeated-dose and reproductive toxicology studies with ulipristal acetate.............................. 38

Table 14 Overview of design of efficacy studies ................................................................................... 46