1 baCKGROUND
The proposed indication for the transdermal testosterone system is for the “treatment of hypoactive sexual desire disorder in surgically menopausal women receiving concomitant estrogen therapy.”
1.1
Definition of FSD
Over the years, there has been uncertainty as to exactly what constitutes a female sexual disorder or dysfunction (FSD). The World Health Organization's International Statistical Classification of Diseases and Related Problems (ICD-10) suggests that sexual dysfunctions are "the various ways in which an individual is unable to participate in a sexual relationship as he or she would wish." The main categories of sexual dysfunction include lack of sexual desire, sexual aversion disorder, failure of genital response (arousal disorder), orgasmic dysfunction, dyspareunia, and excessive sexual drive. The DSM-IV suggests that sexual dysfunctions are "disturbances in sexual desire and in the psychophysiologic changes that characterize the sexual response cycle and cause marked distress and interpersonal difficulty." The dysfunctions include hypoactive sexual desire, sexual aversion, female arousal disorder, female orgasmic disorder, dyspareunia, and vaginismus.
In 1999, the new American Foundation of Urologic Disease (AFUD) FSD diagnostic and classification system was proposed. The AFUD definitions state that disorders must be associated with personal distress, and may be either acquired or lifelong (chronic). The many causes of FSD can be broadly categorized into the following: vascular, neurological, psychogenic, and hormonal-endocrine. The diagnosis of FSD, according to AFUD, requires the clinician to obtain a detailed patient history that defines the problem and identifies causative or confounding conditions and important psychosocial information. The presence of more than one dysfunction should be explored as considerable interdependence may exist. The 4 major components of FSD according to the AFUD classification are the following:
1. Sexual desire disorder [hypoactive sexual desire disorder, HSDD]
2. Sexual arousal disorder [FSAD]
3. Orgasmic disorder [FSOD]
4. Sexual pain disorder [no common acronym]
1.1.1 Hypoactive Sexual Desire Disorder
Hypoactive sexual desire disorder (HSDD), the proposed indication for Intrinsa, is the persistent or recurring deficiency (or absence) of sexual fantasies, thoughts and/or desire for, or receptivity to, sexual activity, which causes personal distress. The cause may be either physiological or psychological or a combination of both. Common physiological etiologies include hormone deficiencies, medications, and surgical interventions. Any disruption of the female hormonal milieu caused by these etiologies can result in decreased sexual desire. The lack of, or a decrease in, sexual desire may also be secondary to poor sexual arousal and response, or to pain associated with sexual activity. HSDD is sometimes a psychologically or emotionally based problem that can result from a variety of reasons, including a history of sexual abuse or trauma. For instance, depression and the treatment of depression are common problems in women with low sexual desire. Another factor may be difficulty with inability to attain or maintain sufficient sexual excitement, a condition known as female sexual arousal disorder (FSAD).
1.2
FDA Guidance
In May 2000 the FDA distributed the first draft guidance for industry for the "Clinical Development of Drug Products for FSD" (see Appendix 1). Although the definition of FSD was continuing to evolve at that time (and still is evolving), emphasis was placed on clearly defining the component or components of FSD that would be targeted for developing therapies and the potential subgroups (e.g., age, premenopausal vs. menopausal; different hormonal therapy) that might respond differently to therapy. Relatively strict inclusion and exclusion criteria were encouraged. The guidance states that personal distress should be measured to ensure appropriate patient selection for trial participation but should not serve as the primary endpoint for establishing effectiveness.
FDA Guidance
recommendations for the clinical development program and clinical trial design
for FSD therapies included the following:
1. Instruments, questionnaires, scales that are used for diagnosis and endpoints should be developed, tested, and validated in women with FSD and should be able to differentiate between normal women and women with different components of FSD
2. Primary endpoints should be statistically significant and clinically meaningful over time and related to the components of FSD being studied
3. The primary endpoint should include change in the number of satisfactory sexual events over time [from baseline to end of treatment] compared to placebo
4. Sexual
events or encounters include:
a) satisfactory sexual intercourse
b) sexual intercourse resulting in
orgasm
c) oral sex resulting in orgasm
d) partner-initiated or self
masturbation resulting in orgasm
5. Endpoints based on health-related quality of life (HRQL) claims should be linked to clinically meaningful objective endpoints
6. Two controlled Phase 3 trials of 6 months treatment duration should be conducted to support an NDA
7. Pre-treatment baseline assessment period of 4-8 weeks
8. Use of a daily diary to record all sexual activities
1.3
Agreements with Applicant
Table 1 below is a brief tabular summary of the major interactions between the Division and Procter and Gamble Pharmaceuticals, Inc. (P&GP). Instrument development and validation were completed for the 3 most important endpoints in the Phase 3 trials. Issues that were raised by the Division at the end-of-Phase 2 meeting, with the Phase 3 protocols, and at the pre-NDA meeting were addressed by the Applicant. The Applicant conducted their development program consistent with the Division's May 2000 draft guidance and subsequent advice from the Division. The following were key issues that were raised in discussions with the Applicant:
1. Conducting the Phase 3 trials primarily in the U.S., because of the concern for major cultural differences in female sexuality in non-U.S. countries.
2. Establishing and validating the diagnosis of HSDD separate from the other major components of FSD
3. The importance of establishing a minimally important clinical difference (MICD) to support the primary endpoint and to help define the responder analysis
4. Meeting the ICH guideline for long-term exposure; adding follow-up visits for safety after treatment ends
5. Need for a responder analysis as a secondary analysis to support the primary endpoint analysis
6. Handling missing data; the last observation carried forward (LOCF) method was changed to satisfy the Division
7. Need for additional assessments of androgenic effects, including virilization and voice changes
Table 1 Regulatory Activity
|
IND #59, 232 (Procter & Gamble Pharmaceuticals,
Applicant) |
|
|
Date |
Topic |
|
16 Jul 99 |
Applicant Pre-IND meeting (IND
#59,232) |
|
8 Dec 99 |
Telecon re instrument validation and
Phase 2 protocol |
|
5 Dec 01 |
End-of Phase 2 (EOP2) meeting; fax
to Applicant on 30 Nov 01 |
|
3 Apr 02 |
FDA response to Applicant follow-up
to EOP2 meeting (letter) |
|
5 Aug 02 |
FDA comments on Phase 3 protocols
(letter) |
|
11 Dec 02 |
FDA feedback on tradename and
validation of diagnosis of HSDD (letter) |
|
26 Jun 03 |
Pre-NDA meeting |
|
21 Jun 04 |
NDA received |
2 Clinical development
It has been reported in
several national U.S. surveys that the proportion of menopausal women having
low sexual desire (HSDD) ranges from 7-33%.
Testosterone levels in populations of menopausal women with and without
low libido have shown overlapping ranges of levels regardless of the libido
status. Testosterone levels alone have
not been shown to have a predictable value for diagnosing HSDD or
characterizing the severity of the condition. As noted earlier, HSDD is
diagnosed by a careful medical and psychosocial history, symptoms, and the
associated distress.
2.1
Testosterone Therapy for HSDD
In the 1980s and 1990s
there were a few reports of small studies using intramuscular or subcutaneous
testosterone to treat HSDD in menopausal women.
Treatment resulting in increased sexual desire and sexual activity as
measured by non-validated instruments for sexual function was often associated
with supraphysiologic serum testosterone levels.
2.2
Applicant’s Early Clinical Development Program
Because there was no
approved therapy available for this indication, the Applicant embarked on a
clinical program to develop a testosterone transdermal system (TTS) for the
treatment of HSDD in surgically menopausal women. A transdermal delivery was selected for its
ability to deliver a relatively steady dose of testosterone that is not
affected by first pass effects of liver metabolism. The pharmacokinetics (PK) of
testosterone from the transdermal system were evaluated in single and multiple
dose studies, in standard PK and population PK studies, for durations of 4 days
to 12 months, at different application sites (abdomen or buttocks), over a
range of testosterone doses. Overall,
there were 3 bioavailability and 3 PK studies.
2.3
Dose Selection
In Phase 2 studies, the
Applicant investigated a range of doses.
The 150 mcg/day dose was not effective, and the 450 mcg/day dose
provided no clear benefit beyond that of the 300 mcg/day dose. Based on these observations, the Applicant
selected a dose of 300 mcg/day for their Phase 3 clinical trials.
2.4
Instrument Development and Validation
Following the FDA’s Guidance on FSD, which states it is important to use validated instruments for assessing responses to FSD therapy in specific target populations, the Applicant developed three psychometric instruments for use in surgically menopausal women in the US, Canada, Europe and Australia. These instruments were designed to measure efficacy endpoints in women with HSDD in surgically and naturally menopausal women. Table 2 lists these 3 instruments.
Table 2 Instruments Used to Measure Response to Treatment
The FDA Draft Guidance stresses that the primary
endpoint for assessing the effectiveness of therapies for FSD is the number of
satisfactory sexual events. The number
of satisfactory events, the primary endpoint of the Applicant’s two major Phase
3 trials, was assessed using the Sexual Activity Log (SAL). The SAL is a record of sexual activity from the previous 7 days. The determination of "satisfaction"
was made by the subject herself, rather than by her partner or a
clinician. The completed weekly diary
was collected every 4 weeks (from the preceding 4 weeks) throughout the 24-week
trials.
The Profile of Female Sexual Function (PFSF) contains 37 questions that
measure subjective aspects of HSDD in the 7 separate domains listed in the
table. The number of questions per
domain ranges from 9 for Desire to 3 for Arousal and Concerns. The Personal Distress Scale (PDS) contains 9
items in a single domain and measures personal distress associated with a
patient's lack of interest in sex. Based
on the subject’s experience and feelings over the preceding 30 days,
subjects filled out the PFSF and PDS at Weeks 0, 4, 8, 12, and 24 in the Phase
3 trials. The PFSF and PDS scores for
each domain were then normalized so that they ranged from 0-100. Scores of 0, 20, 40, 60, 80, and 100 for each
domain correspond, on average, to the following categories of response:
"Never," "Seldom," "Sometimes,"
"Often," "Very Often," and "Always,"
respectively. A decrease in the PDS
score indicates a decrease in a subject's distress.
Based on their validation study, the Applicant believes that the 3 instruments were shown to be valid, consistent, and reliable for the measurement of HSDD in both naturally and surgically menopausal women. Appendix 2 contains the PDS and the items from the Desire domain of the PFSF.
2.5
Overview of Clinical Trials
The clinical program to
evaluate the efficacy of TTS in the treatment of HSDD in surgically menopausal
(SM) women consisted of seven trials (see Table 3),
two of which evaluated multiple dose levels.
The two Phase 2b and the two Phase 3 trials were
similar in design and used the three instruments developed by the Applicant in
surgically menopausal women. The two blinded, placebo-controlled Phase 3
studies (2001133 and 2001134) were the major studies submitted to support
efficacy and safety. They each enrolled
over 500 women. These studies were conducted utilizing the 300 microgram dose
identified as the optimal dose in the earlier Phase 2b studies.
There were two special
studies linked to the Phase 3 trials. A
subset of 132 subjects (68 placebo and 64 active treatment) from the Phase 3
24-week studies was evaluated in a clinical relevance study (CMKUS030993) to
determine whether they experienced meaningful benefits during study
participation. The goal of this
sub-study was to determine the minimally important clinical difference (MICD)
for several parameters. The open label extension studies each included a
blinded 13-week "withdrawal study" from weeks 52-65 to evaluate the
persistence of treatment effect in a total of 205 women. All were positive responders on active
treatment during weeks 24-52 (see Section 4.9).
Table 3 List of Controlled, Blinded Efficacy Studies
|
Study Phase/ # |
N @
Testosterone dose (mcg/day) |
N @ Placebo dose |
Estrogen
Therapy |
Comments |
|
II a T96006 |
N= 75 @ 150 N= 75 @ 300 |
N= 75 |
Oral CEE |
12 wk @ each dose;
crossover |
|
II b 1999068 |
N= 107 @ 150 N= 110 @ 300 N= 111 @ 450 |
N= 119 |
Oral only |
300 mcg/day was the
lowest, safest effective dose |
|
II b 1999092 |
N= 37 @ 300 |
N= 39 |
Transdermal only |
Small European study |
|
III 2001133 |
N= 283 @ 300 |
N= 279 |
Oral and transdermal |
24-week pivotal |
|
III 2001134 |
N= 266 @ 300 |
N= 266 |
Oral and transdermal |
24-week pivotal |
|
Sub-studies of 2001133 and 2001134 |
|
|
|
|
|
CMK030993 Exit interview study |
N= 64 @ 300 |
N= 68 |
Oral and transdermal |
Meaningful Rx benefit
(MICD)* |
|
Withdrawal study |
N= 102 @ 300 |
N= 103 |
Oral and transdermal |
Persistence of Rx benefit-
withdrawal |
|
Total |
N= 771@ 300** |
N= 778 |
|
|
Safety of the
testosterone transdermal system (TTS) was monitored in clinical trials for
periods of 6 months (957 subjects) and 12 months (494 subjects) as described in
the safety section of this review. After the completion of the two Phase 3
12-month trials, P&G has elected to conduct long-term safety surveillance
(open-label) of subjects treated with TTS for up to an additional 3 years. This surveillance is currently on-going (321
women are enrolled beyond 12 months).
3 Clinical Trial Design
3.1
Description of Phase 2 Trial Protocols
Study 1999068 was a randomized, double blind, placebo-controlled multicenter trial investigating the effects of three TTS doses on sexual outcome measures using the SAL and PFSF. The 447 subjects had all undergone a hysterectomy and oophorectomy and had low libido. The study consisted of a 8-week pre-treatment period followed by a 24-week efficacy period and a 28-week safety extension period. Routine laboratory and androgen/estrogen hormonal levels were followed from baseline through the 24 weeks.
Study 1999092 was a randomized, double blind, placebo-controlled multicenter trial investigating the effects of 300 mcg/day on sexual outcome measures using the SAL and PFSF. The 77 subjects had all undergone a hysterectomy and oophorectomy, had low libido, and were on transdermal estrogen therapy (ET). The study consisted of a 8-week pre-treatment period followed by a 24-week efficacy period. Subjects were stratified into 2 groups prior to randomization based on their dose of ET (≤0.05 mg, >0.05 mg). Routine laboratory and androgen/estrogen hormonal levels were followed from baseline through the 24 weeks.
3.2
Description of Phase 3 Trial Protocols
The two Phase 3
studies were nearly identical in design (clinical laboratory tests differed
slightly between the studies). Each was
a multicenter, multinational study conducted in SM women with HSDD. Each was based on a 24-week, randomized,
double-blind (DB), placebo-controlled (PC), parallel-group design to assess
efficacy and safety. Each was followed
by a 28-week open label (OL) extension period to assess safety.
Subjects were stratified based on their use of oral or
transdermal ET. Within each stratum,
subjects were randomly assigned in a 1:1 ratio to receive 300 mcg/day TTS or a
placebo patch. Subjects applied the
investigational TTS to their abdomen twice weekly (each patch was worn for
approximately 3-4 days). Upon completion
of the 24-week DB efficacy and safety period of the study, subjects receiving
placebo were switched to 300 mcg/day TTS, while the active cohort remained on
active treatment. The subjects and
study site personnel remained blinded to the initial randomized treatment
throughout the open label portion of each study.
The primary
objective of each study was to assess the efficacy of 300 mcg/day TTS in
treating HSDD in SM women on concomitant oral or transdermal estrogen
therapy. Efficacy was assessed by the
change in the 4-week frequency of total satisfying sexual events (SSEs) from
baseline to Week 24. Key secondary
objectives were:
1.
personal distress as measured by the
PDS score
2.
sexual desire as measured by the PFSF
The frequency of satisfactory sexual events was recorded
on the SAL that was completed by subjects at home on a weekly basis and
returned to the clinical sites at the next scheduled visit. The PFSF and PDS were completed at the
clinical sites at baseline (Week 0) and Weeks 4, 8, 12, and 24. Safety was evaluated by monitoring adverse
events (AEs), routine clinical laboratory measurements, vital signs, and
physical examinations. Skin appearance
at the most recent abdominal patch application site was evaluated at each
clinic visit for patch site symptoms of irritation. Objective assessments of androgenic effects
on the skin (increases in hair growth at the lip and chin, facial depilation,
and degree of facial acne vulgaris) were also evaluated in each study. Serum samples were analyzed in each study at
baseline and Weeks 12 and 24 for determination of free, total, and bioavailable
testosterone, SHBG, free and total estradiol, and estrone.
3.3
Inclusion/Exclusion Criteria
3.3.1 Inclusion Criteria
Inclusion criteria were developed to ensure that subjects entering the study were
surgically menopausal, satisfied major diagnostic criteria for acquired
(not chronic) HSDD, and were in stable relationships in which partner factors
would not preclude the possibility of demonstrating a treatment effect.
Women were
screened for study participation according to the following inclusion criteria
at Week -8 (Visit 1) unless otherwise specified. Eligible women must have:
1)
been 20 to 70 years old and in
generally good health based on medical history, physical examination, and
laboratory evaluation;
2)
undergone bilateral
salpingo-oophorectomy and hysterectomy at least 6 months prior to screening and
had no physical impediment to sexual function for at least 3 months prior to
screening (documented evidence of
surgery had to be provided). If the
surgical report was not available, a history consistent with removal of both
ovaries was to be obtained. Attempts to
obtain the surgical report were documented;
3)
been receiving a stable dose of ET for
at least 3 months prior to screening with the intention of maintaining that
regimen.
·This treatment should have resulted in, on average, less than 3 moderate
to severe hot flashes per day.
·Acceptable therapies included approved oral estrogens and approved
transdermal estrogen patch regimens.
·Compounded estrogen preparations, selective estrogen receptor modulators
(SERMs), or phytoestrogens preparations were not to be substituted for
the ET requirement;
4)
been, in her own judgment, in a stable
monogamous sexual relationship that was perceived to be secure and
communicative, for at least 1 year prior to study entry. The relationship was to be with the same
partner who was sexually functional, both psychologically and physically, and
expected to be physically present (i.e.,
available for sexual activity at some time during a 24-hour day) at least 50%
of each month during the 8-week pretreatment and 24-week efficacy period of the
study;
5)
answered affirmatively to ALL five of
the following questions:
1.
Before your ovaries were removed,
would you say that in general, your sex life was good and satisfying?
2.
Since your ovaries were removed, do
you feel you have experienced a meaningful loss in your level of desire for
sex?
3.
Since your ovaries were removed, do
you feel you have experienced a significant decrease in your sexual activity?
4.
Are you concerned about or bothered by
your current level of desire for or interest in sex?
5.
Would you like to see an increase in
your level of interest in or desire for sex and sexual activity?
6)
if ³ 40 years of age,
had a clinically acceptable screening bilateral mammogram (no evidence of
malignancy) as determined by the local radiologist (subjects could have
submitted a mammogram done up to 2 months prior to screening). Subjects under 40 years of age at screening
could have elected to have mammograms if they wished, but these were not
required for study entry;
7)
had a clinically acceptable Pap smear
as read by a central cytology facility (no evidence of malignancy or squamous
intraepithelial lesions) if the cervix was present. A Pap smear at study entry
could have been performed on subjects without a cervix at the discretion of the
investigator;
3.3.2
Exclusion
Criteria
Exclusion criteria were
developed to ensure that psychological or physical factors, other than low
testosterone, that could cause hypoactive sexual desire were not present. Potential study subjects with medical
conditions that might cause them to be at increased risk for adverse events
(AEs) were also excluded, as were subjects taking drugs or nutritional supplements
that were likely to affect sexual function.
Women were screened for study participation according to
the following exclusion criteria at Week -8 (Visit 1) or as specified. Eligible women must not:
1)
have had dyspareunia not alleviated by
lubricants, any physical limitations, or sexual trauma since their oophorectomy
that would have interfered with normal sexual function;
2)
have been experiencing any chronic or
acute life stress relating to any major life change, such as recent loss of
income or the death of a close family member, that could have, in the opinion
of the investigator, significantly interfered with sexual activity;
3)
have had significant psychiatric
disorder (including mild depressive disorder, as evidenced by a score of ³ 14 on the Beck Depression Inventory-II [BDI-II]), or had a significant
alcohol or drug dependency and/or been receiving pharmacologic treatment for
such illness or disorder;
4)
have had evidence of clinically
significant organic disease on the history and/or physical examination that
would have, in the opinion of the investigator, prevented the patient from
completing the study, or otherwise affected the outcome of the study. Subjects could not have had any major
illness, active gallbladder disease, gynecological or breast surgery, including
excisional biopsies, within the last 6 months;
5)
have used within the last 12 weeks any
medications/preparations that could have affected sexual function or otherwise
interfered with interpretation of study results.
6)
have used tablet or powder forms of
phytoestrogens for less than 12 weeks prior to Week -8 (Visit 1). No use or stable use of phytoestrogens for 12
weeks or longer was acceptable;
7)
have used (averaging more than once a
week) in the past 30 days the following preparations: dehydroepiandrosterone (DHEA), melatonin, or
other drugs or supplements that could have, in the opinion of the investigator,
affected sexual function;
8)
have received marketed or
investigational oral, sublingual, topical, transdermal, injectable, or vaginal
androgen therapy at any time during the past 3 months, or investigational
implantable androgen therapy at any time in the past 7 months;
9)
have had current severe dermatological
problems (e.g., severe or cystic acne) or had a known or suspected
hypersensitivity or allergy to any adhesive or any of the constituents of the
transdermal systems;
10)
have had a history of breast cancer or
estrogen-dependent neoplasia (e.g., endometrial cancer) or any gynecological
cancer at any time before study entry or other cancer (except basal or squamous
cell carcinoma) within the last 5 years;
11)
have had diabetes, a history of
cerebrovascular disease, thromboembolic disorders, myocardial infarction, or
angina at any time before study entry or thrombophlebitis within the last 5
years;
12)
have had a thyroid-stimulating hormone
(TSH) value at screening above the upper limit of normal confirmed by a free T4
outside the normal laboratory range (subjects with an abnormal TSH, normal free
T4, and no clinical signs or symptoms of thyroid disease, with or without
replacement treatment, could have been admitted to the study);
13)
have had, in the opinion of the
investigator, clinically significant abnormal pretreatment laboratory
parameters (a single repeat assay was allowed if an assay result was
questionable) that would have materially impacted the patient’s ability to
participate in the study;
14)
have had the following laboratory
values:
· serum creatinine > 2.5 mg/dL
· serum total bilirubin ³ 2 times the upper limit of normal
· alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 times the upper limit of normal; or
15)
have previously participated in Study
1999068 or 1999092 or have participated in a clinical trial within 30 days or
received an investigational medication within 30 days (women participating in
observational studies, however, could have been included).
Division comment:
· In the Phase 2 studies T96006 and 1999068, per protocol, all the women had documented low serum testosterone levels [free T <3.5 pg/mL; normal range is 0.9-7.3]. This free T criterion was dropped in the Phase 3 studies because the Applicant’s Phase 2b experience indicated that almost no potential study subject had baseline T levels exceeding the level set. Baseline serum testosterone parameters were obtained, however, as were testosterone levels at Weeks 12 and 24 during the 2 controlled Phase 3 trials.
3.4
Schedule of Assessments
The Schedule of Visit Procedures for the Phase 3 clinical trials is listed in Table 4.