Female Viagra, another neuroleptic (downer) with a special indication

Pharma loves downers.  They are addicting and make the patient dependent on their doctor by causing cognitive impairment.  The FDA has approved downers for most conditions either as a primary treatment or adjunct treatment.  Flibanserin “most common reported adverse events included dizziness, nausea, fatigue, sleepiness…” Wiki.  We can now ad a downer to treat lob libido.  It is an SSRI, a serotonin reuptake inhibitor, the favored downers prescribed for 2 decades. 

At the bottom of this page is how a product which was unanimously denied by the FDA review committee can get approval 5 years later.  It was based on a combination of junk science that showed increased satisfying sex (contrary to earlier studies) and pharma funded so-called consumer groups doing a lobbying campaign to Congress and the FDA. 

 http://www.oregonlive.com/today/index.ssf/2015/06/fda_panel_backs_female_viagra.html

FDA panel backs 'female Viagra' drug

flibanserin but warns of side effects

AP June 4, 2015 

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, MPH^1,2; Kathryn E. Flynn, PhD³; G. Caleb Alexander, MD, MS^4,5

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 pre-established 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.

^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^

Without going into what has been developed else as to the market science published in journal, I will simply states that it is all market dressed up as science, what I call “tobacco science.”  As with all drugs that have a neuroleptic action, the manufacturer of the drug claims that it produces a beneficial balance of neural transmitters.  This is pure sales pitch; the science behind it is missing as to how these putative changes produced the desired safe and beneficial results.  The system is too complex as the passage from Wikipedia below demonstrates.   “Flibanserin acts as a full agonist of the 5-HT_1A receptor (K_i = 1 nM) and, with lower affinity, as an antagonist of the 5-HT_2A receptor (K_i = 49 nM) and antagonist or very weak partial agonist of the D₄ receptor (K_i = 4–24 nM).^{[14][15][16][17} .... demonstrating regional selectivity, and has been found to increase dopamine and norepinephrine levels and decrease serotonin levels in the rat prefrontal cortex, actions that were determined to be mediated by activation of the 5-HT_1A receptor.^[14] As such, flibanserin has been described as a norepinephrine-dopamine disinhibitor (NDDI).^[17][20]  The proposed mechanism of action refers to the Kinsey dual control model of sexual response.^[21] Various neurotransmitters, sex steroids, and other hormones have important excitatory or inhibitory effects on the sexual response. Among neurotransmitters, excitatory activity is driven by dopamine and norepinephrine, while inhibitory activity is driven by serotonin. The balance between these systems is of significance for a normal sexual response. By modulating serotonin and dopamine activity in certain parts of the brain, flibanserin may improve the balance between these neurotransmitter systems in the regulation of sexual response.^[22][23]“  So how can a drug which fails to work get passed  On June 18, 2010, a federal advisory panel to the U.S. Food and Drug Administration (FDA) unanimously voted against recommending approval of flibanserin, citing an inadequate risk-benefit ratio. The Committee acknowledged the validity of hypoactive sexual desire as a diagnosis, but expressed concern with the drug's side effects and insufficient evidence for efficacy, especially the drug's failure to show a statistically significant effect on the co-primary endpoint of sexual desire.^[26]”  The latest clinical trial, the one used by the FDA asked a very fuzzy the question about monthly satisfying sexual experiences:

“There were two ways that the sexual benefit was measured in the studies. The first was a daily diary, the other was a monthly estimate. As a researcher, I think it’s ridiculous to ask women to measure their sexually satisfying experiences based on their memory of the past month. I can remember my daily experiences over the last week, but couldn’t accurately remember them over the exact timeframe of one month. The daily diary found no significant improvement compared to placebo, but the monthly measure found a small improvement: an average of less than one additional satisfying sexual experience per month. That small benefit might be worthwhile for a drug without risks, but that is not true of Addyi [Flibanserin]” In These Times 2/3/16.

Given that the drug is a downer, the memory of events a month out is bound to be inaccurate, and given the phenomena known as breaking blind, which means that those who are on the active drug know it, and those on a sugar pill know it, the answers to the question don’t accurate report their sexual satisfaction.  Breaking blind for a neuroleptic drug is over 80%[1]  Thus asking a question about past month’s sexual performance based on memory and the expectations of benefit by those drugged with Flibanserin will have satisfying sex, this method will produced more favorable recollection than those receiving a sugar pill.  Given how poor positive the results for the question, the net effect really was quite negative for Flibanserin.  

Yes it is a tranquilizer because it main side effects:  “The most commonly reported adverse events included dizziness, nausea, fatigue, sleepiness, and trouble sleeping.  Flibanserin was originally developed as an antidepressant,^[24][25] before being repurposed for the treatment of HSDD.” Wikipedia.  Sleepiness and fatigue are hallmarks of a tranquilizer and nearly all drug marketed as antidepressants are sleep inducing tranquilizers.[2]    Do you need to know more??  Upcoming will be a section on Neuroleptic drugs or read Prof. Gotzsche Deadly Psychiatry and Organized Denial or Prof. David Healy Pharmageddon.