Flibanserin: The Female Viagra is a Failed Me-too Antidepressant

Emily Wheeler
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This article is co-authored by Emily Wheeler, Madeline Brodt, Shannon Peters, and Lisa Cosgrove.

Since a Food and Drug Administration (FDA) advisory committee, on June 4, recommended approval of flibanserin (AddyiTM), there have been numerous editorials and news stories about the controversies surrounding the first “pink Viagra” poised to hit the market. Here, we seek to understand the process and financial incentives that led the advisory committee to recommend its approval. If approved by the FDA,  Sprout Pharmaceuticals will heavily market it as a treatment for a new disorder in DSM 5: Female sexual interest/arousal disorder.

Flibanserin, a serotonergic drug, was initially in clinical trials as an antidepressant. Despite its history of being a “thrice failed antidepressant,” Sprout persevered and used the “finding” that some women in the drug trials said they experienced a slight increase in sexual desire as the reason to repackage the drug. Flibanserin was soon in clinical trials for Hypoactive Sexual Desire Disorder (HSDD), an indication listed in the previous edition of the Diagnostic and Statistical Manual of Mental Disorders). Sprout now maintains that HSDD is comparable to the DSM-5’s “Female Sexual Interest/Arousal Disorder,” and that women deserve a drug to treat this disorder.

As part of the attempt to gain approval for its drug, Sprout  initiated an ingenious marketing campaign, “Even the Score,” claiming that there was a sexism inherent in the number of FDA-approved treatments for sexual disorders: 26 for men and “zero for women.” However, this claim was false. There are only 8 drugs that treat male sexual dysfunction, and none are FDA-approved for low libido.

However, the “Even the Score” campaign worked. Sprout was able to get women’s groups to sign on to the idea that getting this drug approved was almost akin to getting Title IX passed. Not surprisingly, Sprout and its marketing tactics have come under fire. Although it is easy to vilify Big Pharma or one drug manufacturer, in order to effect real change it is necessary to uncover the complex system that led the advisory committee recommend that flibanserin be approved for marketing.

One way to understand how drug companies like Sprout are able to game the system so easily is to use the framework of “institutional corruption.” As Harvard Law Professor Lawrence Lessig notes:

“Institutional corruption is manifest when there is a systematic and strategic influence which is legal or even currently ethical, that undermines the institution’s effectiveness by diverting it from its purpose or weakening its ability to achieve its purpose, including…weakening the public’s trust in that institution.” (Lessig, 2013 JLME)

To apply this framework to medicine, it is important to ask: “What economies of influence allow for the commercialization of science that undermine medical and scientific integrity?”

The Economies of Influence Within and Between the FDA and APA

According to the agency website, the “FDA is responsible for protecting the public health by assuring the safety, efficacy, and security of human … drugs.” It is the agency that serves as the “watch dog” for the public when it comes to medical drugs and devices. However, regulatory standards for efficacy are not as strong as many patients and prescribing providers may think: Efficacy is defined in terms of a chosen effect, “which may or may not be clinically relevant” (Bero & Rennie, 1996).

A drug can get approved even if the trials show that on average, people do not experience a meaningful difference in their symptoms. This is because clinical trials rely on statistical rather than clinical significance, and regulatory agencies such as the FDA do not require evidence of clinical significance. In other words, if a survey instrument with a 5-point scale is used to determine if a drug is effective, a small numerical change can be seen as having a “statistically significant” effect. The issue of clinical significance (i.e., does the drug make a meaningful difference) is relevant here: The clinical trials for flibanserin showed that women had a median change of only one more “sexually satisfying” event per month with the drug versus placebo.

The FDA only approves a new drug if there is a specific indication for its use (i.e., if there is a “real” disease that the drug can treat). A significant difference between drugs for male sexual dysfunction and flibanserin is their targeted indications. While drugs like Viagra treat the physical condition “erectile dysfunction,” Sprout is seeking to get flibanserin approved for treating a mental health disorder, a problem of sexual desire that is theorized to be psychological rather than physical. It is worth noting as well when it comes to drugs that treat sexual desire, women will have flibanserin, if the FDA follows the advisory committee’s recommendation, but there are “zero” such pills for men.

Although only individuals who do not have conflicts of interests should be on the voting committee for the approval of a new drug, it is possible, and happens more frequently than most people realize, that a waiver can be submitted. This means that people with a commercial interests in getting a drug approved are making assessments about that drug’s efficacy and safety. This is where the APA, FDA, and Big Pharma become an “unholy trinity” (Angell, 2005). The makers of flibanserin had invested plenty of time and money into its development long before it was tied to treating sexual dysfunction. Sprout, or any drug company in search of a “pink Viagra,” needs a sexual function disorder that is unique to women and that justifies their drug before their research investment can pay off. Enter HSDD and now Female Sexual Interest/Arousal Disorder (FSI/AD).

The DSM and the Pink Viagra: If You Build it They Will Come

It has been convincingly demonstrated that HSDD and FSI/AD are classic examples of “disease mongering” (Moynihan BMJ, Yanchar, & Fugh-Berman, 2014)—creating a disease in order to promote a drug to treat it. Even the former president of the APA, Paul Appelbaum, admitted that, “The flexible boundaries of many psychiatric diagnostic categories, in the absence of definitive diagnostic tests, may encourage expansive definitions of affected populations and create opportunities for industry to promote treatments for people who would not previously been seen as having a disorder.” (Appelbaum & Gold, 2010)

Indeed, the empirical data supporting the validity of HSDD are incredibly sparse (http://www.newviewcampaign.org/). Numerous researchers, clinicians, and policy experts, have questioned the validity of FFD and HSDD. When HSDD was included in the DSM 5 there was a firestorm of controversy because of concerns around disease mongering. There were also concerns about industry influence on the DSM: 69% of the task force members of the DSM—the individuals responsible for decisions about inclusion or exclusion of mental disorders in the latest edition of this manual—had ties to the drug companies that manufacture the medications used to treat mental disorders.

Despite strong concerns about the validity of HSDD and FSI/AD, and criticisms that the APA may be playing handmaiden to industry and engaging in disease mongering, “Even the Score” made powerful claims about the frequency of these “very real” disorders in women. What the campaign failed to mention was that the provenance of these statistics threatens their validity. One statistic stating that 43% of women experience sexual dysfunction was quoting a highly criticized 15 year old study. Another study that found that 1 in 10 women have HSDD was funded by the very pharmaceutical company that initially developed flibanserin, Boehringer Ingelheim (which then sold rights to the drug to Sprout Pharmaceuticals.) The study was also conducted entirely by individuals who were either employees of Boehringer Ingelheim or were paid consultants for the company. Further, pharmaceutical companies supported the development and validation of one of the main assessment tools used to measure sexual dysfunction, the Female Sexual Dysfunction Index, and it is one of the measures utilized in research studies to support flibanserin’s efficacy.

Conclusion: A Pill for no Ill

The economies of influence at play in the case of flibanserin are not unusual; pharmaceutical dollars primarily fund drug research. However, those dollars also fund the “research” that legitimizes HSDD as a valid disorder, and one that can be treated with that little pink pill.

In order to appreciate how this pill has gotten this far, it is necessary to see the economies of influence (e.g., the commercial ties of the DSM task force members), and the systemic practices (i.e., the FDA does not require the measurement and reporting of clinical significance) that have developed. Rather than vilifying drug companies, the framework of institutional corruption shifts the focus to the potential harm done to patients and the loss of public trust and confidence in the integrity of academic medicine. This framework allows us to see the various economies of influence that contribute to those harms and losses, and serves as a call for action to neutralize those influences. This call to action is particularly important because drug companies are, by definition, profit-minded sponsors of clinical research. And regulatory agencies such as the FDA are, in the current industry dominated climate, not able to mitigate companies’ financial incentives to design trials and collect and analyze data in a way that favors commercial, rather than public health, interests. In light of APA’s financial ties to industry, as well as those of the individuals who created the DSM-5, its vision to be the “conscience of psychiatry” is compromised.

In fact, many have commented on flibanserin’s numerous side effects including “fainting and extreme sleepiness” (Edney & Burger, 2015) Further, other serotonergic antidepressants have been linked to birth defects, a disconcerting fact considering that flibanserin will be taken by women of child-bearing age. If Even the Score’s marketing campaign is truly about women’s empowerment, what are they doing to educate women about these serious potential side effects in order to empower them to make an informed decision about whether flibanserin’s benefits outweigh the risks?

These side effects, and the highly questionable risk/benefit profile of the drug, have profound implications for patient health. If the marketing and sale of flibanserin follows the trajectory of other serotonergic drugs, it is doubtful that women will receive genuine informed consent regarding the risks, benefits, and alternatives to taking this drug.

Even the Score?  No; we say Caveat Emptor.

* * * * *

About the Authors:

ewheelerEmily Wheeler, MS, is a doctoral candidate in Counseling Psychology at the University of Massacusetts Boston. She researches the ethics of mental health care policies and practices and queer mental health.

 

madelineMadeline Brodt, MS, recently received her Masters of Science in Mental Health Counseling from University of Massachusetts Boston and is currently working towards her doctorate in Counseling Psychology. She has authored 15 articles and presentations on a variety of issues including sexuality, consent, conflicts of interest, suicidality and trauma. She is also a clinician at Bay State Community Services and Project Safe.

ShannonShannon Peters, MS, is a doctoral candidate in Counseling Psychology at the University of Massachusetts Boston. Her research areas include ethics of mental health research, informed consent practices, and sexual violence.

 

 

lisaLisa Cosgrove, PhD,is a Clinical Psychologist and Professor at the University of Massachusetts, Boston and a former Research Fellow at the Edmond J. Safra Center for Ethics, Harvard University (2010-2015). She has published over 50 articles and book chapters and has co-edited and co-authored casebooks on the ethical and medico-legal issues that arise in organized psychiatry because of academic-industry relationships. She is the co-author, with Robert Whitaker, of Psychiatry under the Influence: Institutional Corruption, Social Injury, and Prescriptions for Reform.

 

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39 COMMENTS

          • Actually wasn’t trying to be sexist. Sexist would mean that I treat girls different from boys. I don’t.

            The comments I was giving in fact indicated I was the opposite of sexist, because I felt girls could enjoy sex and have as much sex as boys. I treat both sexes the same.

            My comments might have seemed ‘hot’ because I was sort of thinking women with problems would benefit most from seeing a sexual therapist, and forcing themselves to have sex. The more sex you have the more you might want to do it. Sort of like brushing your teeth. Its habit forming. Gets easier in time. For those with claimed “sexual dysfunction.”

            The issue is some girls are coming in claiming they aren’t aroused enough and aren’t as into “sex” as they merely think they ought to be. Thats where they could benefit from either helping to realize its ok to be how they are, or teaching them if they so choose how to rev up their engagement in sex. Best way to do it, is do it. 🙂

          • I see a lot of confused people out there. The type that don’t even know who they are or what they are supposed to be. If a person with true sexual dysfunction had that problem, it would be a part of them, a normalcy for them. The problem is, why don’t they accept themselves for who and what they are, – it could be pressure from the media, their relationships, lack of skills, religious issues, parental issues, trauma, or simple you have a normal lack of sexual interest and need to learn how to integrate it into your life.

            The idea behind this drug here is the fda is letting companies design and market any bodily damaging compounds for whatever they want. They did not start off drsigning this drug to be for depression or sexual issues, but at all cost they want to sell it as such because they know they can get doctors to prescribe it and thus they walk away with bank.

            And this is what is going on today. You have people who are selling snake oils and bodily injurous things. They don’t work, but are causing serious harm.

            Next thing we will hear is how this drug has serious withdraw symptoms, how people experienced memoru loss, mania, depression, and anxiety, electrical zaps, vomitting, tiredness, all of it caused by the drug when they were fine before the drugs use.

            I am so tired of it.

            But I understand people have problems. I just am so afraid and angry that they are being swindled and taken advantage of.

  1. By the way erectal dysfunction is largely iatrogenic. It might be mostly man made, as studies have found the condition is caused or significantly worsened by circumcision. Uncircumcised men have significantly less ED, and when they get it it is not as bad.

    So viagra is mostly being used by circumcised men who had their peters damaged as babies.

    No joke:
    https://www.academia.edu/6395137/Adding_Insult_to_Injury_Acquisition_of_Erectile_Dysfunction_from_Circumcision

    Your chance of getting ED is 3, 4.5, or 5 times greater if you are circumcised. And your ED will be significantly worse.

    So ED is mostly man made, requiring “treatment.”

    Womens on the other hand, there is no underlying injury, no mutilation, no medical problem needing fixing, not one that requires an SSRI anyway.

  2. The really sad part is that if this drug is approved many women will take it not knowing how marginally effective and dangerous it is. They will do this because they trust their doctors to do what is best for them. When I was younger I also trusted physicians. No more. Every doctor I go to wants to prescribe drugs for even minor conditions. They never discuss side effects, efficacy or drug interactions. For one thing, to do this would take too long. For another, most physicians know very little about the medications they so freely foist on their patients.

  3. I also object to the sexist comments made earlier.

    I have a feeling that this grossly phony campaign by the drug maker, claiming that approving this worse than useless drug is a “feminist issue,” is eventually going to backfire on them. This Astroturf way of doing things is, I think, going to educate a lot of women (and men) to the tactics of the drug companies that they may not have been paying attention to before.

    It’s the sort of drug whose benefits (nonexistent) and negative effects (many) will be very clear to the kind of people (young women much more likely than average to pay attention to what happens to their bodies when they take a drug) who will be using this. It may become a feminist issue, all right, but a real one, not what the drug company has in mind.

  4. Perhaps a minor point, but the statement in this article that FDA does not consider clinical significance in approval decisions is factually incorrect, and the 20 year old paper cited in support of this statement is at best out of date.

    FDA guidance documents on trial design for different therapeutic areas routinely discuss minimum acceptable thresholds for clinical significance, often providing exact numerical values. The FDA guidance for the development of antiobesity drugs, for example, specifies a minimum average weight loss of 5%.

    In this particular case, setting a numerical threshold is difficult, as the value placed on 0.5 additional “satisfying sexual events” per month will be a very individual one. Overall I think its probably best to allow individuals to make that decision for themselves.

      • Steve, the FDA considers the weight of evidence provided by all trials, though it does consider trials in which a known positive control fails to separate from placebo as a “failed study”.

        If you have an example of a drug that was approved on the basis of two positive studies and 15 that showed harm or no effect, could you share it with us? I’d be fascinated to see it.

        • It was not 15 but if you look at the metananalysis of anti-depressant trials submitted to FDA which was done by Irving Kirsch and colleagues it’s pretty clear that this “consideration” is meaningless. Plus it does not account for the problem that companies don’t need to pre-register and publish all trials so many negative results never see the light of the day.

          • The Kirsch meta analysis was certainly not the only one to address thi question, and in fact most meta analyses of this topic, including those by NICE, the FDA, and the Cochrane Collaboration reached differing conclusions. In any case, I think the quality of the discussion here will be best served by avoiding overstatement and ecaggeration.

  5. Interesting informative article. Thanks.
    What’s not mentioned here is the fact that FDA employees themselves, some entrenched in that bureaucracy for many , many years, come to think of themselves as advocates for the pharmaceutical industry – doing whatever they can to get a drug, or a new use, approved and working to reduce black box warnings, or any sort of stronger warnings.
    Dr. Tom Laughren, head of the psychiatric section of the FDA, spent many years trying to maanipulate that advisory committee to approve the atypical antipsychotics for children and then many more years refusing to put a stronger warning on the label or set up any sort of registry for children. If you read the public documents of committee meetings, you will see that this is the case.

    • Ebl:

      Good point about beaurocrats. We tend to forget that beaurocrats do not need to be accepting bribes to be classified as unfit to fill the role of protecting the public. In federal agencies mandated to protect and manage our national forests it is quite common to encounter individual employees who identify with being employees for the timber industry. They are so old school they can’t even understand the conflict of interest.

  6. It’s an issue of sexism all right. Does any one know the rate at which females are prescribed ineffective psychiatric medications in comparison to their adult male counterparts?
    That this is blessed by the FDA shows how useless that agency has become.

  7. Flibanserin was initially proposed as an antidepressant. In the disclosed side effects this as an antidepressant to the FDA from Boehringer (6/18/10), it is noted that flibanserin caused a decrease in libido (read that as DECREASE, found on page 205 of 248 pages) as a side effect, but there was no INCREASE in libido as a side effect. In the information submitted to the FDA as a sexual enhancement, somehow decreased libido was not a noted adverse effect.

    Boehringer writes that In the Phase IIa depression trials, in which flibanserin failed to show efficacy on the primary
    endpoint, virtually no sexual dysfunction was noted. This is not quite true. Between 0.6% and 1.4%, depending on the dose, of subjects showed reduced libido.

    Reduced libido is a very serious side effect of a drug that offers such minimal proof of improving libido.

    • Well, it’s supposed to activate the serotonin receptor so increase serotonin signalling. SSRIs are well known to increase serotonin signalling by inhibiting the removal the serotonin from the synaptic cleft and they are linked to potentially irreversible sexual dysfunction. My guess is that flibanserin will turn out to do the exact same thing – maybe increase libido in some women while impairing it, sometimes (always?) permanently, in most. Unfortunately we are likely to see this hypothesis tested in real life on real people and that all pretty soon.

      • This article states the Flibanserin causes a decrease in serotonin, and an increase in dopamine and norepinephrine.

        http://www.smithsonianmag.com/smart-news/why-flibanserin-isnt-female-viagra-180955506/

        Does anyone know if this is the same way Wellbutrin works? My experience, and that of others online, was that Wellbutrin could, at least in some people, cause increased libido. Dramatically so, in my case. Which would be a good thing, had it not been misdiagnosed as bipolar.

        • It’s supposed to be an agonist of serotonin receptor so it should increase the serotonin signalling, kind of like SSRIs do. Which is not to say that we have any clue what it actually does in the organism given the fact that in higher concentrations it also binds other receptors and we have no idea what other indirect effects it has or how the body compensates for it. The only thing I would guess is that it may very well induce sexual dysfunction like the SSRIs do.

          • So, B, do you think that Smithsonian article is wrong? (I don’t know.) All I know is there are quite a few blogs / articles, and actually a lot of patient queries, regarding Wellbutrin and increased libido. I didn’t not find these with the Flibanserin in a quick google search. And I’m pretty certain Wellbutrin causes changes with dopamine, norepinephrine, and serotonin.

            Emily, do you or your co-authors happen to if these two drugs affect the brain in a similar, or dissimilar, manner?

          • For what these drugs really do to any given person your guess is as good as mine. They bind many receptors and have different effects on them and then there’s also a big black box called our body which can react to the presence of the drug in many ways, enhancing or reducing it actions or even going all the way to the otehr side. All psych drugs have people reporting all kinds of effects, from the “desired” ones to completely opposite ones through everything in between and bizzare.
            One thing is sure – I’d never want to take it.

        • Wellbutrin sure does do that. It’s funny that GSK was fined 3 billion from promoting is as a weight-loss and sex-enhancing drug when it is one for Drugs.com says “increased/decreased libido” is a side effects. That’s close.

          Oddly enough, I fainted last time I was on it.

          The neurotransmitter story with Wellbutrin is confusing. First, it’s a chemical cousin of amphetamine in that it’s a substituted cathinone which means it’s also a substituted amphetmine. (From what I gather, substituted means it’s almost the the same, but a few atoms are swapped out for different ones.) Wikipedia goes on to say

          “bupropion and its metabolites act as non-competitive antagonists of several neuronal nicotinic acetylcholine receptors”

          and states that it has insignificant dopamine-related actions in the brain, doing most of its work on norepinephrine.

    • Yes, 0.6% to 1.4% showed reduced libido, compared to 0.6% of those treated with placebo. The absolute numbers were 4/718 on placebo and 3/179 on the highest flibanserin dose.

      Suggesting that flibanserin causes libido decreases based on this data is a little bit like suggesting a coin is loaded because it came up heads twice in a row.

  8. Flibanserin is just another SSRI. It has been so well documented in all the literature I’ve read on psychiatric drugs and it’s plentiful that the main side effect of SSRI’s is sexual dysfunction. I’ve witnessed it in every person prescribed an SSRI, and in myself. Anyone, please look up how many American’s are on an SSRI, the numbers are staggering. This is marketing madness! Women not familiar with these types of drugs are going to have no idea of the side effects, adverse reactions, and especially the withdrawals. Of course, after your’e on them for any length of time, it’s going to have withdrawal symptoms and they are horrendous. I have been involved with the mental health care field for over 35 years as a patient and I hear, and have experienced myself the horrors of taking all the psychiatric drugs. Our psychiatrists or doctors do no inform patients of the true side effects, adverse reactions, and especially the withdrawals. They leave us to suffer.

  9. “As part of the attempt to gain approval for its drug, Sprout initiated an ingenious marketing campaign, “Even the Score,” claiming that there was a sexism inherent in the number of FDA-approved treatments for sexual disorders: 26 for men and “zero for women.” However, this claim was false. There are only 8 drugs that treat male sexual dysfunction, and none are FDA-approved for low libido.”

    Btw, that strongly reminds me of the campaign that tobacco companies directed at women in order to convince them to smoke. Same bs masquerading as gender equality:
    http://pialogue.info/books/Century-of-the-Self.php
    You can also listen to Noam Chomsky on the propaganda industry. Btw, people who have participated in creating the propaganda system were psychologists.

  10. The posts that I have seen about Addyi are by people who haven’t taken it. That’s understandable because it’s so new.

    My wife is 62 and post-menopause. Her sexual desire has been low for over 10 years and was tired of not have those wonderful feelings anymore.

    She started taking Addyi about as soon as it was offered last fall and, actually, liked the psychological effects of the drug. She said that she it made her feel more relaxed and less edgy.

    It seemed to take a couple of months for the sexual effects to start kicking in. As her sex partner, I can report that her interest in sex is real and growing. She initiates sex almost everyday and we are having a truly great time!! I’m 69, quite fit, and have a strong libido and keeping up with her is a fabulous challenge. Sex is the healthiest, happiest gift that you can give your marriage. If the chemistry of older age is causing your desire and enjoyment to wane, take advantage of this breakthrough. It works and it’s wonderful.