WASHINGTON — The drug industry's decade-spanning search for a
female equivalent to Viagra took a major step forward Thursday, as government
experts recommended approval for a pill to boost sexual desire in women. The
first-of-a-kind endorsement came with
safety reservations, however, due to drug side effects including fatigue, low
blood pressure and fainting. The panel
of Food and Drug Administration advisers voted 18-6 in favor of Sprout Pharmaceutical's [bought rights from Boehringer
Ingleheim] daily pill, flibanserin, on the condition that the company develops
a plan to manage its risks. The recommendation
is a major victory for a drug sometimes hailed as "female Viagra,"
but which has been plagued for years by concerns of lackluster effectiveness
and safety issues. The FDA has rejected the drug twice since 2010. And a
similar panel of FDA experts voted unanimously against the drug five years ago. [See
bottom article from 2010]. Thursday's vote is non-binding but the FDA
often follows the advice of its experts. An official decision is expected in
August.
FDA's experts acknowledged that flibanserin's effect is not very strong,
but said there is a need for FDA-approved drugs to address female sexual
problems. "These are very modest
results," said Dr. Julia Heiman of the Kinsey Institute at Indiana
University. "But on the other hand, even modest results can make a lot of
difference when you're at a certain point in the clinical problem." In general,
women taking flibanserin reported
between 0.5 and 1 more sexually satisfying event per month, compared with women
taking a placebo. They also scored higher on questionnaires measuring desire
and scored lower on measures of stress. Flibanserin,
which acts on serotonin and other brain
chemicals, was originally studied as
an antidepressant, but then repurposed as a libido pill after women
reported higher levels of sexual satisfaction.
The effort to trigger sexual interest through brain chemistry is the
drug industry's latest attempt to address women's sexual problems.
^^^^^^^^^^^^^^^^^
This article and the one below show how pharma
works the
system to create a condition, then market a drug that long term is worse than
nothing at all. The modest improvement
in a six week trial doesn’t last as side effect increase and tolerance
increase. And unlike Viagra, neuroleptic
drugs such as serotonin reuptake inhibitors are taken daily. SSRis have found
a number of indications
based upon sleeping more, they include as a muscle relaxant, a pain medication,
hypertension, and for nicotine addiction.
For example, one smokes less when sleeping longer.
http://health.usnews.com/health-news/family-health/sexual-and-reproductive-health/articles/2010/06/16/flibanserin-failure-female-viagra-drug-disappoints
Flibanserin Failure: Female Viagra Drug Disappoints
US News, Health Section
6/16/2010
A new drug
designed to boost sexual desire in women is controversial for some and eagerly
awaited by others, but it's hit a potentially serious snag. The drug didn't boost women's
desire any more than a placebo in two clinical trials. The Food and Drug Administration posted the clinical trial
results on its website today in advance of a committee meeting on Friday, when
a panel of experts will vote whether or not to recommend approval of the drug
called flibanserin. (The FDA usually follows the recommendations of its expert
panels.) Although there was a slight
increase in the number of sexually satisfying events flibanserin users had each
month, the FDA staff who reviewed the results said the so-called response rate
isn't "particularly compelling."
In a statement
posted on the FDA website, manufacturer Boehringer Ingelheim maintains that
flibanserin really works, while acknowledging it's better at increasing a
woman's "global desire" than "the intensity of [her] acute
episodes of desire." That phrasing suggests the drug's effects are, well,
rather subtle.
Trouble is, flibanserin has side effects
that may outweigh its tepid benefits. About 15 percent of flibanserin users in
the experimental trial stopped taking the drug because of bad reactions like
dizziness, nausea, anxiety and insomnia, compared to 7 percent of the placebo
users. Side effects were heightened in those who used the drug at the same
time they were taking other medications, such as anti-fungal treatments,
hormonal contraceptives, and
antidepressants. Flibanserin itself was
originally designed to be an antidepressant, but past clinical trials found
that it didn't alleviate depression.
While
flibanserin's fate rests in the hands of the FDA, Boehringer Ingelheim has
kicked off a widespread education campaign to make us aware that having a low
sex drive is a real medical condition that affects "approximately 1 in 10
women"—a statistic disputed as overinflated by some sexual health experts.
The company has hired actress Lisa Rinna to be the poster girl for low libido
and funded the "Sex, Brain, Body" website that has an
"educational toolkit" that urges women to please talk
to their doctors if they think
they have a problem.
[Not in the
Mood? You Could Have Hypoactive Sexual Desire
Disorder]
Interestingly, the
Discovery Channel has also hopped on the
bandwagon to educate their viewers about low sexual desire disorder. This documentary [advertising]
aired
on its
stations last month and was funded by, yes, Boehringer Ingelheim. John Whyte, a
physician who oversees Discovery's continuing medical education (CME) and
patient education programs, told U.S. News that
Discovery maintained full
editorial control of the film, which has the feel of an infomerical but doesn't
mention flibanserin. Whyte said that the
drug manufacturer was allowed to review the film before it aired "as a
courtesy" and that "they
could suggest experts for us to interview." One of the experts
featured prominently is Sheryl Kingsberg, a clinical psychologist at Case
Western Reserve University School of Medicine who is a paid consultant for Boehringer
Ingelheim and is
participating in their clinical trials of flibanserin. Another person
interviewed is Phyllis Greenberger, head
of the Society for Women's Health Research, which received funding from the
drug manufacturer to produce the "Sex, Brain, Body" website.
If the Discovery
program had mentioned flibanserin by name,
Boehringer Ingelheim could have ended up in hot water with the FDA, which
restricts marketing of drugs it hasn't approved. While the Discovery program doesn't identify the unapproved
drug, it does show women who were somehow helped by their doctors—it doesn't
say specifically how. One woman proclaimed, "I felt vital again. I felt energetic
again. I had that drive."
When asked if any of the women featured in the film were participants in the
flibanserin clinical trials, Elizabeth Hillman, senior vice president of
communications at Discovery responded, "we really don't know." She
did admit, though, that this film made by Discovery's CME department isn't
"a traditional Discovery Channel documentary" in terms of its
journalistic rigor.
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
The panel, they added, never
discussed much about the way Sprout used patient-reported data to establish an
increase in sexual desire for the primary efficacy endpoint, switching from a
daily diary to a questionable four-week recall method using a desire subscale
of the Female Sexual Function Index [FSFI] in a follow-up study.
JAMA. Published online July 06, 2015.
doi:10.1001/jama.2015.8405
http://jama.jamanetwork.com/article.aspx?articleid=2389384
Evaluation
of Flibanserin: Science and Advocacy at
the FDA
Walid
F. Gellad, MD, MPH1,2;
Kathryn E. Flynn, PhD3; G.
Caleb Alexander, MD, MS4,5
On June 4, 2015, the US Food and Drug Administration
(FDA)
convened a scientific advisory committee meeting to review the efficacy and
safety of flibanserin, a new molecular entity for the treatment of hypoactive
sexual desire disorder (HSDD) in premenopausal women. This was the second such
meeting of the committee regarding a product that had twice been rejected by
the FDA due to an unfavorable risk-benefit profile. After the day-long hearing,
the advisory committee voted 18 to 6 in favor of recommending approval of the
drug, provided certain risk management options were implemented. The FDA is not
bound to this recommendation and has indicated that it will rule on the
product’s application by the end of August. Regardless of the outcome, the
FDA’s decision is certain to join other controversial regulatory decisions at
the intersection of science, policy, and advocacy. In this Viewpoint, we
discuss the history of flibanserin and provide insight about the regulatory
process from the point of view of 3 of the advisory committee members at the
FDA meeting.
Flibanserin was initially
developed as an antidepressant, but it
failed to demonstrate efficacy.
In phase 2 trials of patients
with depression, the drug was more effective than placebo in terms of study participants’
responses to the question “How strong is your sex drive?”1 Development of the drug then
shifted to a potential treatment for HSDD, defined as “persistently or
recurrently deficient or absent sexual fantasies and desire for sexual
activity” accompanied by “marked distress and interpersonal difficulty” that is
not accounted for by a nonsexual mental disorder, medication, severe
relationship stress, or general medical condition.2 In 2013, the Diagnostic
and Statistical Manual of Mental Disorders, 5th edition, combined HSDD with female sexual arousal disorder into female
sexual interest/arousal disorder. The disorder has no FDA-approved treatments,
and the FDA has recognized the condition as an area of unmet medical need.3
In the original FDA application for use of
flibanserin for HSDD in
2009, both pivotal phase 3 trials failed
to show statistically significant improvement [about 20%, more in a small
trial] compared with placebo in a
primary end point assessing sexual desire using a single item in a daily
electronic diary. Although the other primary end point (the reported number
of satisfying sexual events) and the secondary end point (the desire subscale
of the Female Sexual Function Index [FSFI]) met preestablished efficacy
thresholds [slightly better than a placebo], the FDA denied approval after a unanimous
advisory committee vote
against approval.
The drug was resubmitted to the FDA for review
in 2013 with
results from a new phase 3 trial using FSFI desire as the co-primary desire end
point instead of the daily diary, showing statistically significant but
numerically small treatment differences at 24 weeks compared with placebo (an
increase of 0.3 on the FSFI desire subscale [range, 1.2-6.0] and an increase of
0.5 satisfying sexual events per month). In an FDA “responder analysis” of the
phase 3 trials, after accounting for the placebo effect, approximately 8% to 13%
of women were at least “much
improved” on at least 1 of the primary outcomes. [Would you take a drug if you
had merely a 10% chance of benefiting?]
A variety of safety concerns were raised
during the 2013 FDA
review, including a risk of hypotension, syncope, and somnolence among users of
the product, as well as the potential for adverse effects when flibanserin is
taken with alcohol or CYP3A4
inhibitors such as oral contraceptives [ethinyl estradiol, EE2] or fluconazole.
The drug is to be taken once daily at bedtime, which lowers the risk or
consequences of sedation-related adverse events. The risks of syncope were
relatively low in the pivotal clinical trials (0.5% flibanserin vs 0.3%
placebo), but the overall risks of
sedation or hypotension-related adverse events were substantially higher
with flibanserin vs placebo (28.6%
flibanserin vs 9.4% placebo). In addition,
the trials were limited to
generally healthy women not taking benzodiazepines, sleep aids, narcotics, or a
number of other medicines, and, as with many trials, they were of short
duration relative to the potential length of time that flibanserin could be
indicated. Given these concerns, as well as overall modest efficacy, the FDA
again rejected the product application and recommended additional safety
studies.
For the most recent FDA review, no new efficacy
data were
presented. Instead, the sponsor of flibanserin provided additional safety data,
including a study suggesting the absence of next-day driving impairments, a
comparison of the product’s adverse effect profile with that of other marketed
products, and an analysis confirming the potentiating effects of alcohol on
adverse events. Although the driving study was reassuring, isolated comparisons
of safety across products can be misleading because FDA product reviews are not
fundamentally comparative in nature. Notably, the alcohol interaction study
took place in a sample of 25 healthy volunteers, only 2 of whom were women.
Several additional features of
the regulatory path involving flibanserin are noteworthy. First, following the
FDA’s second rejection of flibanserin in
2013, an advocacy group called Even the Score was formed to advocate for what
it called “gender equality” in access to treatments for sexual dysfunction.4 The group, initially created
through the efforts of a consultant to flibanserin’s manufacturer who formerly
directed the FDA’s Office of Women’s Health, promoted the claim that there
are 26 approved medications for male
sexual dysfunction but none for women. The claim has been rejected by the FDA,
because there are no approved
products for low sexual desire in men, and the 26 medications include multiple
formulations of testosterone. Although flibanserin is not the first product
to be supported by a consumer advocacy group in turn supported by
pharmaceutical manufacturers, claims of gender bias regarding the FDA’s
regulation have been particularly noteworthy,
as have the extent of advocacy efforts ranging from social media campaigns to
letters from members of Congress.5
The second noteworthy feature
in the FDA application for flibanserin was the use of a patient-reported
outcome of sexual desire as the primary efficacy variable for approval. Sexual
desire is known only to the person experiencing it, and patient-reported
outcomes measure such concepts without interpretation from others. Patient-reported
outcomes are increasingly prioritized in research and other drugs have been
approved with these outcomes as primary end points (although none based on
sexual desire). Among all new molecular entities and biologic license
applications approved by the FDA from 2006-2010, Gnanasakthy et al6 identified 17% (20 of 116
products) that granted patient-reported outcome claims as the primary outcome
on the approved label. The complicating factor in evaluating flibanserin
centered around the switch in the primary desire end point from a daily diary
rating the person’s most intense desire in the first application to a 4-week
recall of the frequency and intensity of desire as measured by the FSFI desire
subscale. The FDA raised some concerns about the optimization of the FSFI for
assessing desire, including the content validity and recall period, but the
recent advisory committee did not focus discussion on either the switch in
primary end points or the validity of the FSFI.
A final concern regarding flibanserin relates
to its likely use in
clinical practice, and this was a major issue for the committee. Although there
are few reliable estimates of the prevalence of HSDD, the product, as with
others, is all but certain to be used off-label among a broader population of
women than has been studied, many of whom may not fulfill formal diagnostic
criteria for HSDD and many of whom may have conditions or concomitant
medication use that increases the risk of adverse events. The concerns about
off-label use were reinforced by public speakers at the meeting who expressed
their need for flibanserin, while at the same time reporting conditions that
may have excluded them from on-label treatment, such as a cancer diagnosis or
postmenopausal status.
The FDA regulates drug approval
and marketing, not the practice of medicine. The Committee’s discussions about
flibanserin and off-label use highlight the challenge that the FDA encounters
when considering a product that may help a subpopulation of patients, but also
has a risk-benefit profile that may make it unacceptable for broader use.
Despite the positive advisory committee vote, recommendations for approval were
accompanied by support for Risk Evaluation and Mitigation Strategies (REMS),
including potentially requiring prescriber and pharmacy certification to
prescribe or dispense the product. However, despite the Advisory Committee’s
emphasis on risk management after approval as a means to increase the product’s
safe use, there remains a paucity of evidence about the ability of most REMS
programs to fulfill this promise.7
These features of flibanserin—the Even
the Score advocacy
campaign, the shifting efficacy end points and use of a patient-reported
outcome measure, the tenuous risk-benefit balance among the studied population
and potential for widespread off-label use, and an unmet medical need—are not
totally unfamiliar territory for the FDA, but represent a challenge when they
occur simultaneously. What makes the approval process for flibanserin even more
unique is the politically charged atmosphere in which the FDA will decide how
all these trade-offs should best be navigated.
http://www.eventbrite.com/e/speaker-series-green-thumb-how-to-grow-pot-tickets-17603709168?aff=SBB
It
ain't what it seems to be. It is another neuroleptic
drug. The sex drug for women is amphetamines. They want sex on it
all night and longer. I use to give them 125 mgs of pure amphetamine
(they are all about the same) and it was all night action. Barb, then
Ruta, then Tina, and a few girlfriends all did it with me. Always the
same results. I am curious if the affects now are different now that you are
older???
