- Email: [email protected]
Men, women, and testosterone: Why did the FDA fail Intrinsa?
E ED D II T TO OR R II A AL L
Men, women, and testosterone: Why did the FDA fail Intrinsa? Machelle M. Seibel, MD
F
or most people, sex is a very imporTABLE 1 tant part of their lives. As Cole PorTestosterone products in the pipeline ter implied, “Birds do it, bees do it, even educated fleas do it.” Product/manufacurer When available So when men can’t do it, they go to their Intrinsa Patch/P&G Failed initial approval; undetermined launch doctor or click on one of the countless spam e-mails that clutter their inboxes each day MDTS spray/Vivus Final studies 2005; available 2006? and buy one of three FDA-approved drugs to LibiGel gel/BioSante In late phase studies; available 2007? remedy the problem. According to Business Week (2-28-05), sales of Viagra for 2004 were Androsorb cream/Novavax In midphase studies; available? $1.7 billion, with Cialis and Levitra trying hard Estratest pill/Solvay Approved for menopausal symptoms; to catch up. sexual dysfunction studies begun Spending upward of $55 million on directto-consumer ads seems like a good investment. Interestingly, these drugs have changed men’s sexual frequenhen a woman has a cy expectations of their female partners and created a disparity in desire that didn’t exist 15 years ago. reduction in sexual When a woman has a reduction in sexual desire or arousal, or simply wants to keep up with her libido-enhanced partner, what FDAdesire, what FDA-approved approved medication does her doctor prescribe? That’s the problem. There isn’t one. Last December, an FDA advisory committee decidmedication does her doctor ed not to recommend approval of Procter & Gamble’s Intrinsa, a prescribe? That’s the problem. testosterone patch for improving women’s declining libido.
W
There’s a need for treatment, no doubt Sexual desire in women is known to decline with age, at least in part due to declining testosterone. Dr. John Buster’s article in this issue of SRM (see page 3) explains that about half of testosterone is derived from the adrenal glands and half is supplied largely by the ovarian stroma. About 10 million women have had oophorectomy in the United States, and each year some 300,000 more women undergo the procedure. Studies suggest that 10% of spontaneously menopausal women experience a loss of sexual desire. But a survey conducted by Prime Plus/Red Hot Mamas in 2000 found that 45% of postmenopausal women younger than 55 years of age indicated significant declines in sexual desire. In my menopause practice, hypoactive sexual desire disVOL. 3, NO. 1, MAY 2005
There isn’t one.
I
n my menopause practice, hypoactive sexual desire
disorder and female sexual arousal disorder are at least as commonly complained of as hot flashes. Sexuality, Reproduction & Menopause
1
Editorial order (HSDD) and female sexual arousal disorder are at least as commonly complained of as hot flashes.
A thumbs down from the FDA
Machelle M. Seibel, MD Department of Obstetrics & Gynecology University of Massachusetts Medical School Memorial Campus 119 Belmont Street, 4th Floor Worcester, MA 01605 [email protected] (617) 916-1880 office (617) 964-4549 fax
With such a great need and no existing FDAapproved drug in place, why did the FDA not okay the testosterone patch? Several reasons were cited: • Not sure it worked that well. Intrinsa worked for only about half the women who used it. Well, 50% of millions of women that it might work for is still a lot of women. Consider also that 30% to 50% of the time, Viagra failed to help certain groups of men. • Modest increased frequency of “satisfying sexual events.” The patch increased the frequency of satisfying events from four times a month to five (placebo increased them from three times to four). The difference, the FDA said, was statistically significant but might not be “clinically meaningful.” Unlike men who need an erection in order to engage in intercourse, women can have sex whether or not they are aroused, rendering frequency of sexual acts a poor indicator of successful treatment. • Placebo effect? P&G found that 52% of patch users reported improved sexual desire, compared with 31% of placebo users. These findings led panel members to believe that the difference between Intrinsa and placebo wasn’t that vast and led committee member Steven Nissen, MD, a car-
A
n estimated 20% of testosterone gel sales are to women. There are likely many times that number of testosterone prescriptions filled at compounding pharmacies across the country. diologist from the Cleveland Clinic, to recommend that P&G “consider marketing the placebo” (The Wall Street Journal, December 14, 2004). It seems that everyone forgot that the real sex organ is the brain, and even an ersatz pill can sometimes be helpful. Even Viagra has been reported to show a 25% placebo effect in men. • Is it safe? Having just come off the recent recall of Vioxx and still reeling from the Women’s Health Initiative, the FDA was 2
Sexuality, Reproduction & Menopause
cautious. At some level this is understandable. But the FDA itself reported that as many as 145,000 women have received prescriptions for a testosterone gel that is approved for men, and the dose is 10 to 20 times higher than the dose proposed for women. It is estimated that at least 20% of testosterone gel sales are to women. There are likely to be many times that number of testosterone prescriptions filled at compounding pharmacies across the country. In those situations, doses vary considerably and women self-medicate the amount they rub on if they don’t get the desired effect, risking side effects from higher than prescribed dosages. Intrinsa’s dose was physiologic for women, and the most common side effect was a minor skin reaction at the site of the patch. Less than 1% of women dropped out because of side effects. While follow-up on Intrinsa was of short duration, I know that testosterone has been given routinely off-label for the 25 years I’ve been in practice, and its use was going strong when I arrived on the scene. So where does Intrinsa go from here? P&G initially studied the patch on 1,100 women. The company intends to submit a new NDA for Intrinsa for the treatment of HSDD in menopausal women. The new application will contain data from five major phase III clinical trials. These include two trials in surgically menopausal women on concomitant estrogen therapy (which were evaluated during the December 2004 Advisory Committee hearing); two trials in naturally menopausal women on concomitant estrogen therapy with or without a progestin; and one trial in both surgically and naturally menopausal women who are not on a systemic estrogen therapy. The total number of women studied will be approximately 5,000. Then, at some future date, P&G will try again. A few other testosterone products are in the pipeline of other drug companies (see Table 1). Until they are approved, men with sexual dysfunction will continue to choose from among three FDAapproved drugs; and women with reduced sexual desire and arousal and low serum testosterone levels will continue to be treated with testosterone off-label or do without. It’s time for women with sexual dysfunction to have the same FDA-approved treatment with testosterone that men have. ■ VOL. 3, NO. 1, MAY 2005
Men, women, and testosterone: Why did the FDA fail Intrinsa? Machelle M. Seibel, MD
F
or most people, sex is a very imporTABLE 1 tant part of their lives. As Cole PorTestosterone products in the pipeline ter implied, “Birds do it, bees do it, even educated fleas do it.” Product/manufacurer When available So when men can’t do it, they go to their Intrinsa Patch/P&G Failed initial approval; undetermined launch doctor or click on one of the countless spam e-mails that clutter their inboxes each day MDTS spray/Vivus Final studies 2005; available 2006? and buy one of three FDA-approved drugs to LibiGel gel/BioSante In late phase studies; available 2007? remedy the problem. According to Business Week (2-28-05), sales of Viagra for 2004 were Androsorb cream/Novavax In midphase studies; available? $1.7 billion, with Cialis and Levitra trying hard Estratest pill/Solvay Approved for menopausal symptoms; to catch up. sexual dysfunction studies begun Spending upward of $55 million on directto-consumer ads seems like a good investment. Interestingly, these drugs have changed men’s sexual frequenhen a woman has a cy expectations of their female partners and created a disparity in desire that didn’t exist 15 years ago. reduction in sexual When a woman has a reduction in sexual desire or arousal, or simply wants to keep up with her libido-enhanced partner, what FDAdesire, what FDA-approved approved medication does her doctor prescribe? That’s the problem. There isn’t one. Last December, an FDA advisory committee decidmedication does her doctor ed not to recommend approval of Procter & Gamble’s Intrinsa, a prescribe? That’s the problem. testosterone patch for improving women’s declining libido.
W
There’s a need for treatment, no doubt Sexual desire in women is known to decline with age, at least in part due to declining testosterone. Dr. John Buster’s article in this issue of SRM (see page 3) explains that about half of testosterone is derived from the adrenal glands and half is supplied largely by the ovarian stroma. About 10 million women have had oophorectomy in the United States, and each year some 300,000 more women undergo the procedure. Studies suggest that 10% of spontaneously menopausal women experience a loss of sexual desire. But a survey conducted by Prime Plus/Red Hot Mamas in 2000 found that 45% of postmenopausal women younger than 55 years of age indicated significant declines in sexual desire. In my menopause practice, hypoactive sexual desire disVOL. 3, NO. 1, MAY 2005
There isn’t one.
I
n my menopause practice, hypoactive sexual desire
disorder and female sexual arousal disorder are at least as commonly complained of as hot flashes. Sexuality, Reproduction & Menopause
1
Editorial order (HSDD) and female sexual arousal disorder are at least as commonly complained of as hot flashes.
A thumbs down from the FDA
Machelle M. Seibel, MD Department of Obstetrics & Gynecology University of Massachusetts Medical School Memorial Campus 119 Belmont Street, 4th Floor Worcester, MA 01605 [email protected] (617) 916-1880 office (617) 964-4549 fax
With such a great need and no existing FDAapproved drug in place, why did the FDA not okay the testosterone patch? Several reasons were cited: • Not sure it worked that well. Intrinsa worked for only about half the women who used it. Well, 50% of millions of women that it might work for is still a lot of women. Consider also that 30% to 50% of the time, Viagra failed to help certain groups of men. • Modest increased frequency of “satisfying sexual events.” The patch increased the frequency of satisfying events from four times a month to five (placebo increased them from three times to four). The difference, the FDA said, was statistically significant but might not be “clinically meaningful.” Unlike men who need an erection in order to engage in intercourse, women can have sex whether or not they are aroused, rendering frequency of sexual acts a poor indicator of successful treatment. • Placebo effect? P&G found that 52% of patch users reported improved sexual desire, compared with 31% of placebo users. These findings led panel members to believe that the difference between Intrinsa and placebo wasn’t that vast and led committee member Steven Nissen, MD, a car-
A
n estimated 20% of testosterone gel sales are to women. There are likely many times that number of testosterone prescriptions filled at compounding pharmacies across the country. diologist from the Cleveland Clinic, to recommend that P&G “consider marketing the placebo” (The Wall Street Journal, December 14, 2004). It seems that everyone forgot that the real sex organ is the brain, and even an ersatz pill can sometimes be helpful. Even Viagra has been reported to show a 25% placebo effect in men. • Is it safe? Having just come off the recent recall of Vioxx and still reeling from the Women’s Health Initiative, the FDA was 2
Sexuality, Reproduction & Menopause
cautious. At some level this is understandable. But the FDA itself reported that as many as 145,000 women have received prescriptions for a testosterone gel that is approved for men, and the dose is 10 to 20 times higher than the dose proposed for women. It is estimated that at least 20% of testosterone gel sales are to women. There are likely to be many times that number of testosterone prescriptions filled at compounding pharmacies across the country. In those situations, doses vary considerably and women self-medicate the amount they rub on if they don’t get the desired effect, risking side effects from higher than prescribed dosages. Intrinsa’s dose was physiologic for women, and the most common side effect was a minor skin reaction at the site of the patch. Less than 1% of women dropped out because of side effects. While follow-up on Intrinsa was of short duration, I know that testosterone has been given routinely off-label for the 25 years I’ve been in practice, and its use was going strong when I arrived on the scene. So where does Intrinsa go from here? P&G initially studied the patch on 1,100 women. The company intends to submit a new NDA for Intrinsa for the treatment of HSDD in menopausal women. The new application will contain data from five major phase III clinical trials. These include two trials in surgically menopausal women on concomitant estrogen therapy (which were evaluated during the December 2004 Advisory Committee hearing); two trials in naturally menopausal women on concomitant estrogen therapy with or without a progestin; and one trial in both surgically and naturally menopausal women who are not on a systemic estrogen therapy. The total number of women studied will be approximately 5,000. Then, at some future date, P&G will try again. A few other testosterone products are in the pipeline of other drug companies (see Table 1). Until they are approved, men with sexual dysfunction will continue to choose from among three FDAapproved drugs; and women with reduced sexual desire and arousal and low serum testosterone levels will continue to be treated with testosterone off-label or do without. It’s time for women with sexual dysfunction to have the same FDA-approved treatment with testosterone that men have. ■ VOL. 3, NO. 1, MAY 2005