The marketing of a disease: female sexual dysfunction
http://www.100md.com
《英国医生杂志》
1 1312 21st Street NW, Apt 4, Washington, DC 20036, USA raymond.moynihan@verizon.net
The pharmaceutical industry's dreams of making large profits from treating female sexual dysfunction are starting to look like premature speculation
Introduction
One of the biggest hurdles for drug makers in this area is showing a big enough benefit over placebo to outweigh concerns about short or long term side effects. These concerns are made more acute by recent revelations about hormone replacement therapy, antidepressants, and anti-arthritis drugs. At the December meeting, the FDA highlighted concerns about the potential long term risks of cardiovascular disease and breast cancer for those using the testosterone patch.13 FDA reviewing medical officer Lisa Soule said that use of the patch was associated with higher than normal testosterone activity for an important minority of women in the company trials. She pointed out small, potentially troubling changes in several laboratory measurements and other indices, including blood pressure, among women using the patch and oestrogen. The changes suggested that the drug combination may increase the risk of cardiovascular disease. Soule concluded that the short term nature of the 24 week placebo controlled randomised trials meant the regulator was "Unable to answer many questions about the safety of testosterone."
Expert adviser Steve Nissen, from the Cleveland Clinic, told the same meeting that in his view, based on the available data from the company's trials: "There was a high probability of excess cardiac risk with this product." Another panel member, Joanne Dorgan, noted that the heightened testosterone levels in some women using the patch could increase the risk of breast cancer. The trial data also showed small increases over placebo in minor side effects including acne, hair growth, and weight gain.14
Yet, in contrast, abstracts of data from the company's trials, presented by leading sex researchers at key international conferences, have simply concluded the testosterone patch is "well-tolerated." They have not mentioned potentially serious harms and have played down the small increases in milder side effects. The most recent abstract, presented in October 2004, states: "Overall, adverse event reports were similar in the testosterone and placebo groups."15 Similarly, the slides from the company sponsored medical education package refer to the benefits of the patch but not its side effects. Sidney Wolfe, from the US consumer watchdog Public Citizen, told me that Proctor and Gamble is "Presenting a distorted view of its product by trivialising its risks."
While the possibly important risks of testosterone have been trivialised, the potentially modest benefits have been overblown. None of the key trials have been published in peer reviewed journals, but abstracts describing the company's data have been presented at several medical conferences in the United States and elsewhere in the past two years. The same data from the pivotal phase III trials have been presented at least twice, and data from one of the smaller phase II trials have been presented at least three times. Enthusiastic media coverage has often followed these presentations, most notably when a press release carried a headline suggesting the patch caused a "74 per cent increase in frequency of satisfying sexual activity.12 This figure misleadingly describes the benefits in relative terms and gives no sense of the absolute benefits.
In absolute terms the trials showed the testosterone patch increased the amount of satisfying activity for women by around two "episodes" a month compared with baseline—but only one extra episode compared with the placebo response (table). Moreover, this extra episode was on top of a baseline of around three sexual events a month, causing some researchers to question whether the women enrolled in the trials were really dysfunctional. "Three events per month, that's not a little," University of Amsterdam associate professor Ellen Laan told me, "That's quite average in the sort of long term relationships the women enrolled in these trials were having."
Preliminary results of 24 week randomised controlled trials of testosterone patch 300 μg/day in surgically menopausal women13
Harvard University associate professor Jan Shifren, a strong advocate of the testosterone patch, rejects the focus on the modest increases in sexual activity. She told me the key issue is how women feel about their desire problems. "The most important finding is the decrease in distress." Testosterone caused a significant decrease in distress compared with placebo, as measured by a company funded scale. Yet as FDA reviewers pointed out, the decrease over placebo was only 6 or 7 points on a 100 point scale. On a separate measure, testosterone increased a woman's level of desire over placebo by only 5 or 6 points on a 100 point scale, raising serious questions about the meaningfulness of these purported benefits (table).14
Although the FDA advisers ultimately voted to accept the patch benefits as "clinically meaningful," they unanimously rejected the company's data as inadequate to assess long term safety, and unanimously recommended the agency not to approve the drug. Proctor and Gamble's Plummer says the company is working with the regulator on the patch and looking to its leadership.
Controversy about the conflicts of interest
Wilson R. Feminine forever. New York: M Evans, 1966.
Writing Group for the Women's Health Initiative. Risks and benefits of estrogen plus progestin in healthy menopausal women. JAMA 2002;288: 321-33.
National Women's Health Network. Taking hormones and women's health, choices, risks and benefits. Washington DC: National Women's Health Network, 1995.
Moynihan R. The making of a disease: female sexual dysfunction BMJ 2003;326: 45-7.
Moynihan R. FDA panel rejects testosterone patch for women on safety grounds. BMJ 2004;329: 1363.
Moynihan R, Heath I, Henry D. Selling sickness: the pharmaceutical industry and disease mongering. BMJ 2002;324: 886-91.
PR Newswire. Antares Pharma partner completes phase II clinical trials for testosterone transdermal gel in female sexual dysfunction. 29 Jun 2004. www.forbes.com/prnewswire/feeds/prnewswire/2004/06/29/prnewswire200406291030PR_NEWSNET_PH_PHTU018.html (accessed 14 Jan 2005).
Richters J, Grulich AE, deVisser RO, Smith AM, Rissel CE. Sexual difficulties in a representative sample of adults, Austr N Z J Public Health 2003;27: 164-70.
Basson R, Leiblum S, Brotto L, Derogatis L, Fourcroy J, Fugl-Meyer K, et al. Revised definitions of women's sexual dysfunction. J Sex Med 2004;1: 40-8.
Bancroft J, Loftus J, Long J, Distress about sex: a national survey of women in heterosexual relationships. Arch Sex Behav 2003;32: 193-208.
Procter and Gamble Pharmaceuticals. A reporter's guide to testosterone and its role in women's health. www.pgpharma.com/guide_testosterone.pdf (accessed 23 Dec 2004).
Procter and Gamble News Release. Landmark clinical study shows testosterone patch significantly improved sexual desire in surgically menopausal women. www.newswire.ca/en/releases/archive/May2004/04/c8449.html (accessed 23 Dec 2004).
Food and Drug Administration Advisory Committee for Reproductive Drugs. Briefing information for public hearing, 2 December. www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4082b1.htm (accessed 23 Dec 2004).
Food and Drug Administration Division of Reproductive and Urologic Drug Products. Medical review, Intrinsa, NDA 21-769. Nov 2004. www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4082b1.htm (accessed 23 Dec 2004).
Utian W, Braunstein G, Buster J, Lucas J, Simon J. Testosterone transdermal patch improved sexual activity and sexual desire in surgically menopausal women: results from two phase III studies . Annual meeting of International Society for the Study of Women's Sexual health, Atlanta, Georgia, October 2004.
New View campaign. www.fsd-alert.org (accessed 23 Dec 2004).
Daly R, Palmer K. True or false? Women need a form of Viagra. Toronto Star 2004 Dec 8: 1.(Ray Moynihan, journalist1)
The pharmaceutical industry's dreams of making large profits from treating female sexual dysfunction are starting to look like premature speculation
Introduction
One of the biggest hurdles for drug makers in this area is showing a big enough benefit over placebo to outweigh concerns about short or long term side effects. These concerns are made more acute by recent revelations about hormone replacement therapy, antidepressants, and anti-arthritis drugs. At the December meeting, the FDA highlighted concerns about the potential long term risks of cardiovascular disease and breast cancer for those using the testosterone patch.13 FDA reviewing medical officer Lisa Soule said that use of the patch was associated with higher than normal testosterone activity for an important minority of women in the company trials. She pointed out small, potentially troubling changes in several laboratory measurements and other indices, including blood pressure, among women using the patch and oestrogen. The changes suggested that the drug combination may increase the risk of cardiovascular disease. Soule concluded that the short term nature of the 24 week placebo controlled randomised trials meant the regulator was "Unable to answer many questions about the safety of testosterone."
Expert adviser Steve Nissen, from the Cleveland Clinic, told the same meeting that in his view, based on the available data from the company's trials: "There was a high probability of excess cardiac risk with this product." Another panel member, Joanne Dorgan, noted that the heightened testosterone levels in some women using the patch could increase the risk of breast cancer. The trial data also showed small increases over placebo in minor side effects including acne, hair growth, and weight gain.14
Yet, in contrast, abstracts of data from the company's trials, presented by leading sex researchers at key international conferences, have simply concluded the testosterone patch is "well-tolerated." They have not mentioned potentially serious harms and have played down the small increases in milder side effects. The most recent abstract, presented in October 2004, states: "Overall, adverse event reports were similar in the testosterone and placebo groups."15 Similarly, the slides from the company sponsored medical education package refer to the benefits of the patch but not its side effects. Sidney Wolfe, from the US consumer watchdog Public Citizen, told me that Proctor and Gamble is "Presenting a distorted view of its product by trivialising its risks."
While the possibly important risks of testosterone have been trivialised, the potentially modest benefits have been overblown. None of the key trials have been published in peer reviewed journals, but abstracts describing the company's data have been presented at several medical conferences in the United States and elsewhere in the past two years. The same data from the pivotal phase III trials have been presented at least twice, and data from one of the smaller phase II trials have been presented at least three times. Enthusiastic media coverage has often followed these presentations, most notably when a press release carried a headline suggesting the patch caused a "74 per cent increase in frequency of satisfying sexual activity.12 This figure misleadingly describes the benefits in relative terms and gives no sense of the absolute benefits.
In absolute terms the trials showed the testosterone patch increased the amount of satisfying activity for women by around two "episodes" a month compared with baseline—but only one extra episode compared with the placebo response (table). Moreover, this extra episode was on top of a baseline of around three sexual events a month, causing some researchers to question whether the women enrolled in the trials were really dysfunctional. "Three events per month, that's not a little," University of Amsterdam associate professor Ellen Laan told me, "That's quite average in the sort of long term relationships the women enrolled in these trials were having."
Preliminary results of 24 week randomised controlled trials of testosterone patch 300 μg/day in surgically menopausal women13
Harvard University associate professor Jan Shifren, a strong advocate of the testosterone patch, rejects the focus on the modest increases in sexual activity. She told me the key issue is how women feel about their desire problems. "The most important finding is the decrease in distress." Testosterone caused a significant decrease in distress compared with placebo, as measured by a company funded scale. Yet as FDA reviewers pointed out, the decrease over placebo was only 6 or 7 points on a 100 point scale. On a separate measure, testosterone increased a woman's level of desire over placebo by only 5 or 6 points on a 100 point scale, raising serious questions about the meaningfulness of these purported benefits (table).14
Although the FDA advisers ultimately voted to accept the patch benefits as "clinically meaningful," they unanimously rejected the company's data as inadequate to assess long term safety, and unanimously recommended the agency not to approve the drug. Proctor and Gamble's Plummer says the company is working with the regulator on the patch and looking to its leadership.
Controversy about the conflicts of interest
Wilson R. Feminine forever. New York: M Evans, 1966.
Writing Group for the Women's Health Initiative. Risks and benefits of estrogen plus progestin in healthy menopausal women. JAMA 2002;288: 321-33.
National Women's Health Network. Taking hormones and women's health, choices, risks and benefits. Washington DC: National Women's Health Network, 1995.
Moynihan R. The making of a disease: female sexual dysfunction BMJ 2003;326: 45-7.
Moynihan R. FDA panel rejects testosterone patch for women on safety grounds. BMJ 2004;329: 1363.
Moynihan R, Heath I, Henry D. Selling sickness: the pharmaceutical industry and disease mongering. BMJ 2002;324: 886-91.
PR Newswire. Antares Pharma partner completes phase II clinical trials for testosterone transdermal gel in female sexual dysfunction. 29 Jun 2004. www.forbes.com/prnewswire/feeds/prnewswire/2004/06/29/prnewswire200406291030PR_NEWSNET_PH_PHTU018.html (accessed 14 Jan 2005).
Richters J, Grulich AE, deVisser RO, Smith AM, Rissel CE. Sexual difficulties in a representative sample of adults, Austr N Z J Public Health 2003;27: 164-70.
Basson R, Leiblum S, Brotto L, Derogatis L, Fourcroy J, Fugl-Meyer K, et al. Revised definitions of women's sexual dysfunction. J Sex Med 2004;1: 40-8.
Bancroft J, Loftus J, Long J, Distress about sex: a national survey of women in heterosexual relationships. Arch Sex Behav 2003;32: 193-208.
Procter and Gamble Pharmaceuticals. A reporter's guide to testosterone and its role in women's health. www.pgpharma.com/guide_testosterone.pdf (accessed 23 Dec 2004).
Procter and Gamble News Release. Landmark clinical study shows testosterone patch significantly improved sexual desire in surgically menopausal women. www.newswire.ca/en/releases/archive/May2004/04/c8449.html (accessed 23 Dec 2004).
Food and Drug Administration Advisory Committee for Reproductive Drugs. Briefing information for public hearing, 2 December. www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4082b1.htm (accessed 23 Dec 2004).
Food and Drug Administration Division of Reproductive and Urologic Drug Products. Medical review, Intrinsa, NDA 21-769. Nov 2004. www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4082b1.htm (accessed 23 Dec 2004).
Utian W, Braunstein G, Buster J, Lucas J, Simon J. Testosterone transdermal patch improved sexual activity and sexual desire in surgically menopausal women: results from two phase III studies . Annual meeting of International Society for the Study of Women's Sexual health, Atlanta, Georgia, October 2004.
New View campaign. www.fsd-alert.org (accessed 23 Dec 2004).
Daly R, Palmer K. True or false? Women need a form of Viagra. Toronto Star 2004 Dec 8: 1.(Ray Moynihan, journalist1)