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GENDER MEDICINE/VOL. 7, NO. 4, 2010
Commentary
Sex, Gender, and Pharmaceutical Politics: From Drug
Development to Marketing
Jill A. Fisher, PhD1; and Lorna M. Ronald, PhD2
1Center for Biomedical Ethics & Society, Vanderbilt University, Nashville, Tennessee; and 2Interdisciplinary
Studies Program,
John Jay College (City University of New York), New York, New York
Background: Biological sex differences and sociocultural gender norms affect the provision of health
care Copyright Excerpta Medica, Inc, 2010 has been little explicit analysis of the impact of sex differences and gender norms on the regulation of pharmaceutical development and marketing.
Objectives: This article provides an overview of the regulation of pharmaceuticals and examines the
ways that regulatory agencies account for sex and gender in their review of scientific data and marketing materials. Methods: The primary focus is on the US context, but information is also included about regulatory
models in Europe, Canada, and Japan for comparative purposes. Specific examples show how sex differ-ences and gender norms influence scientific and policy decisions about pharmaceuticals.
Results: The United States and Canada were found to be the only countries that have explicit require-
ments to include women in clinical trials and to perform sex-based subgroup analysis on study results. The potential influence of politics on regulatory decisions may have led to an uneven application of stan-dards, as seen through the examples of mifepristone (for abortion) and sildenafil citrate (for erectile dys-function). Three detailed case studies illustrate the importance of considering sex and gender in pharma-ceutical development and marketing: Phase I clinical trials; human papillomavirus quadrivalent vaccine; and tegaserod, a drug for irritable bowel syndrome.
Conclusions: Sex and gender play important roles in pharmaceutical regulation, from the design of
clinical trials and the approval of new drugs to advertising and postmarketing surveillance. However, regulatory agencies pay insufficient attention to both biological sex differences and sociocultural gender norms. This disregard perpetuates inequalities by ignoring drug safety problems that predominate in women and by allowing misleading drug marketing that reinforces gender stereotypes. Recommendations have been made to improve the regulation of pharmaceuticals in regard to sex and gender. (Gend Med. 2010;7:357–370) 2010 Excerpta Medica Inc.
Key words: pharmaceutical regulation, drug development, marketing, direct-to-consumer advertising,
Phase I trials, HPV quadrivalent vaccine, tegaserod, mifepristone, sildenafil citrate. Accepted for publication August 2, 2010. 2010 Excerpta Medica Inc. All rights reserved. scription drugs is permitted. DTCA frequently Pharmaceuticals are an important topic through blurs the line between healthy and unhealthy, which to explore sex and gender in health care. frames health in gendered ways, or minimizes the This article explores the interplay of gender and severity of disease or treatment regimens.4–15 For pharmaceutical regulation to illustrate how sex example, advertisements for the birth control and gender differences in drug development and pill Seasonale®* offer women “freedom” from marketing emerge from biology and politics. The menstruation, by promising only 4 periods a year concept of “pharmaceutical politics” highlights (1 every 3 months).16 As another example, prior to the complex interaction of regulatory agencies a US Food and Drug Administration (FDA) warn- with sociocultural and economic interests to shape ing letter sent on April 27, 2001, some antiretrovi- the medicines that are available and our knowl- ral drugs were advertised in gay magazines with edge about them. To begin with, sex differences hypermasculine images of men participating in and gender norms affect both drug development sports, such as mountain climbing, which are mis- and marketing. By “sex,” we mean the biological leading pictures of what can be a grueling medica- characteristics or differences between men and tion regimen for HIV/AIDS patients.9,12,17 women. By “gender,” we mean the social and cul- Gender has also been incorporated into the tural norms associated with masculinity and femi- industry technique of rebranding existing drugs as ninity. Specifically, some pharmaceuticals are new therapies. To extend the patent protection on designed for only one sex, such as hormonal con- the chemical comprising its blockbuster anti- traceptives for women and erectile dysfunction depressant, Eli Lilly repackaged Prozac®† as a pill medications for men. Other pharmaceuticals are named Sarafem® to treat premenstrual dysphoric
approved for use only in one sex, such as drugs to disorder (PMDD) in women.18 Although premen- treat irritable bowel syndrome (IBS) in women. strual symptoms are unheard of in many parts These often did not start out as single-sex products, of the world, in the United States they became but clinical trial data showed efficacy in just one framed as a medical matter of malfunctioning sex. Beyond the drug approval process, many phar- female biology.19 Like earlier psychopharmaceuti- maceuticals exhibit marked sex differences in their cals dubbed “mother’s little helpers,” Sarafem effectiveness or adverse-effect profiles that emerge advertisements drew on gendered imagery of during clinical use.1 For instance, some drugs seem marital discord and frazzled motherhood that sug- to work better in one sex. This is the case for selec- gested the drug could be a pharmaceutical solu- tive serotonin reuptake inhibitors, a class of drugs tion to women’s domestic problems.20 This mar- utilized primarily to treat depression, which tend keting campaign led to the FDA issuing a warning to be more effective in women than in men.2 letter to Eli Lilly on the grounds that the advertise- Other drugs cause more adverse drug reactions in ments blurred the line between clinically normal women than in men. Specifically, the US Gov- and abnormal behavior and trivialized PMDD.21 ernment Accountability Office (GAO) published a This article begins with an overview of the regu- report in 2001 which found that of the 10 prescrip- lation of pharmaceuticals. While our primary tion drugs withdrawn from the market between focus is on the United States, we also include 1997 and 2001, 8 drugs “posed greater health risks information about regulatory models in Europe, for women than for men” and 4 drugs “had more Canada, and Japan. We describe the ways in which adverse events in women even though they were sex, gender, and politics become woven into phar- widely prescribed to both women and men.”3 maceutical regulation, especially with the inclu- In addition, social and cultural assumptions sion of women in clinical trials and sex-based about gender shape how pharmaceuticals and medical conditions are marketed to patients. This *Trademark: Duramed Pharmaceuticals, Inc. (Pomona, New is especially true in the United States, where direct-to-consumer advertising (DTCA) of pre- †Trademark: Eli Lilly and Company (Indianapolis, Indiana).
analysis of study results. In addition, we describe tory process in an incremental way that ensures the potential influence of politics on regulatory their eventual new drug applications will be com- decisions that may have led to an uneven applica- plete. This has led to the criticism that the FDA tion of standards, as seen through the examples of treats the pharmaceutical industry, instead of the mifepristone (for abortion) and sildenafil citrate American public, as its partner or client, leading to (for erectile dysfunction). Next, we provide 3 de- weaker enforcement of existing regulations.23 tailed case studies that illustrate the importance The United States is 1 of only 2 developed coun- of sex and gender in pharmaceutical development tries (the other is New Zealand) that allow con- and marketing: Phase I clinical trials; human pap- sumer advertising of prescription drugs, and the illomavirus (HPV) quadrivalent vaccine; and tega- FDA is also the agency responsible for regulating serod, a drug for IBS. Finally, we conclude by sum- all industry marketing campaigns. In its oversight marizing problems with and proposing solutions of DTCA, the FDA follows regulations written in for the current system of pharmaceutical oversight the 1960s which state that advertising must be fairly balanced and neither false nor misleading.24 Since 1997, when it changed its guidelines to facilitate DTCA, the FDA has enforced advertising regulations by sending warning letters that ask pharmaceutical companies to stop or alter unbal- Because the United States is the leading market anced or misleading advertising campaigns.25 for the consumption of prescription drugs world- However, these letters are usually sent several wide, the pharmaceutical industry often prioritizes months after advertisements have already been its drug development and marketing strategy according to the rules and guidelines outlined by Although drug development and marketing are the FDA. The FDA regulates how clinical trials are regulated as separate processes, pharmaceutical conducted, which drugs are approved for clinical companies often blur the line between the two.23,26 use, and how pharmaceuticals are marketed. For Through postmarketing trials, physicians receive pharmaceutical companies to bring their products financial incentives to give their patients new to market, they must engage in lengthy research drugs and ask them to fill out surveys.27 Unlike and development to prove that those new phar- more robust Phase IV surveillance studies that serve to generate important information about the The process for transforming chemical molecules safety and effectiveness of drugs newly released on into pharmaceuticals happens in the laboratory the market, the data generated from these post- through bench and animal research as well as in marketing studies have limited scientific value, the clinic through human experimentation. As but companies know that patients often continue products advance through the stages of testing, taking the same drug after the trial has ended and companies submit data and proposed protocols to that physicians prescribe the drug to other pa- the FDA to ensure that the research complies with tients.23 More broadly, the market potential of regulations and will generate the information the prospective new pharmaceuticals strongly influ- FDA eventually needs to approve the products. For ences the therapeutic areas in which companies instance, pharmaceutical companies need suffi- invest their drug development resources.28 cient data from animal studies before they can begin human testing. In addition, companies must show that the products are safe in a limited number While the United States may indeed be the of humans before they can commence larger stud- pharmaceutical industry’s most lucrative market, ies to test the products’ effectiveness. FDA oversight other regions of the world are important for its aims to protect human subjects, but it also assists profits, so companies must navigate multiple reg- pharmaceutical companies throughout the regula- ulatory systems. Pharmaceutical companies can either apply to the European Medicines Agency Although the FDA is often described as the most (EMA), or they can apply to a member country for rigorous regulatory agency in the world, it focuses their drugs to become available throughout Europe its review of new drug applications exclusively on by means of mutual recognition agreements. In safety and efficacy. In contrast, European nations general, approval times are faster for new drugs in and Canada also take into account comparative Europe than they are in the United States. However, effectiveness and the cost of products when decid- Europe also has a higher rate of market withdraw- ing whether to use drugs in their national health al of drugs than does the United States, for exam- systems. While these measures do not keep drugs ple, 12% in Great Britain compared with 3% in the off the market, they do limit their adoption by United States.29 This suggests that accelerating pa- health care providers. Prioritization of cost control tients’ access to new pharmaceuticals leads to more and comparative effectiveness means that new safety issues, and regulatory agencies must bal- drugs are evaluated against preexisting products, helping to determine their clinical utility rather Canada, in contrast, historically has had a more than relying on the free market to do so.32 In 2009 conservative approach to drug regulation, approv- as part of the American Recovery and Reinvest- ing drugs more slowly than the United States and ment Act, the United States earmarked significant therefore withdrawing fewer from the market for sources of new funding for comparative effective- safety reasons. However, Canada’s regulatory agen- ness research through the Department of Health cy, the Therapeutics Products Directorate, has re- and Human Services, especially the National Insti- cently adopted aspects of both the American and tutes of Health and the Agency for Healthcare European models, requiring pharmaceutical com- Research and Quality. It will be interesting to trace panies to pay user fees (like the United States) and how this investment of research dollars might influ- harmonizing its requirements with the EMA. This ence future health care policy in the United States.
change is facilitated by the International Confer- ence on Harmonisation, which emphasizes speed- ing up the approval process even when safety National efforts to regulate drug development are beginning to include explicit attention to biologi- Japan’s Pharmaceutical and Medical Devices cal differences between men and women. In the Agency (PMDA) is the most conservative pharma- 1980s, influenced by the women’s health and HIV/ ceutical regulatory agency worldwide because of AIDS movements, the US regulatory apparatus its compensation scheme and ethnicity require- began not only to lift restrictions on women’s par- ments. Starting in 1979, the original purpose ticipation in clinical trials, but also to incorporate of drug oversight was to compensate victims; the requirements for medical research to include diverse government pays medical expenses, disability populations and document differences based on compensation, and death benefits for injuries and sex and race/ethnicity.33 Whereas federal funding deaths resulting from prescription drug use.30 In mandates the inclusion of women and minorities addition, to market their products in Japan, phar- in clinical research, private-sector research is regu- maceutical companies were required until 2007 lated primarily through applications to the FDA for to complete all their clinical studies in Japan on marketing new drugs or devices. Changes to FDA ethnic Japanese subjects. Now, the PMDA allows requirements were made in the late 1980s and early pharmaceutical companies to complete small- 1990s that lifted restrictions on women’s participa- scale “bridging studies” using ethnic Japanese sub- tion in clinical trials and obliged companies to jects worldwide to confirm that Japanese bod- analyze clinical trial data by sex. Moreover, these ies metabolize the drugs similarly to original trial requirements apply to marketing as well as to prod- subjects’ bodies.31 This recent change is expected uct labeling, which must include any sex-based to speed up drug approval times dramatically in differences that might influence the prescription decisions physicians and patients make.1 Despite these requirements, pharmaceutical companies often because this pharmaceutical has the potential to fail to include information on sex differences in increase the availability of abortions.37 To address their new drug applications, and the FDA fails to this concern, the FDA mandated that mifepristone enforce its requirements before approving new would not be available through a prescription at drugs.34 This effectively means that potential sex pharmacies but only through specially qualified licensed physicians, effectively limiting its use.36 Canada is the only other country to have a For the past 20 years, mifepristone has remained a regulatory approach to sex-based analysis of data politically controversial drug. There have been from clinical trials which is similar to that of the numerous (unsuccessful) bills proposed that would United States. Beginning in 1996, it has required pass laws banning or restricting the use of mifepris- the inclusion of representative numbers of women tone, and its approval and oversight have been the in clinical trials followed by subgroup analysis. subject of Congressional investigation.38 In contrast, the European Union and Japan have The case of sildenafil citrate (Viagra®*) is quite no such mandates. The Medicines and Health- different. The FDA classified the drug to treat care Products Regulatory Agency in the United King- erectile dysfunction as “a major advance in treat- dom explicitly encourages, but does not require, the ment” so that it was eligible for priority review. The FDA granted approval of the product in 1998, less than 6 months after it received the applica- tion, at a time when most drugs took well over a Like most government activities, the approval of year to receive approval. By the end of the year, new drugs is a political process.35 Despite the insti- the adverse-effect profile of sildenafil citrate was tutional infrastructure and scientific processes in becoming increasingly a cause for concern, and place at the FDA, broader politics, including gen- the FDA required the manufacturer to issue a der politics, can influence the outcome of drug warning letter to physicians. Within just several applications. The most striking cases are mifepris- months of the drug’s availability on the market, tone and sildenafil citrate, which together tell 242 deaths were linked to the drug, 130 of which quite different stories about the FDA approval of were in the United States.39 Moreover, the approved FDA label for sildenafil citrate has changed sub- Mifepristone, initially known as RU-486, is a stantially between the years 1998 and 2008 to pharmaceutical that induces abortion. Evidence include passages from postmarketing experience that mifepristone was both safe and effective was about the possibility of heart failure as a result of available in the late 1980s when it was approved taking the drug. Simultaneously, marketing for in France, but the FDA requested that additional sildenafil citrate has broadened the drug’s use studies be conducted.36 After these data were sub- from an impotence treatment to erectile enhance- mitted, the FDA deemed in 1996 that the drug was ment.40 While there are serious risks of taking both safe and effective, but delayed approving it sildenafil citrate and the health benefits of this by stipulating that additional label and manufac- drug for this condition are limited, drug therapy turing information was necessary before the prod- for erectile dysfunction is not politically contro- uct could go to market.37 An additional 3-month versial, and there has been little political will to delay occurred when the supplier of the bulk restrict the use of sildenafil citrate or to remove it material changed, and the FDA requested supple- mentary data to ensure the stability and quality of These 2 cases illustrate how sociocultural norms the product. Mifepristone eventually received about gender can determine the availability of pharmaceuticals. Regardless of how innovative, Given the political clout of antiabortion groups safe, or effective the 2 products are, politics pre- in the United States, mifepristone was seen by many members of Congress as very threatening *Trademark: Pfizer Inc. (New York, New York). vailed in keeping mifepristone off the US market The underrepresentation of women in Phase I for more than a decade. On the surface, it appears clinical trials has several causes. Historical modes that it is simply abortion politics that influenced of paternalism assumed women needed additional mifepristone’s slow progress through the FDA protection in medical research. For example, from approval process. At a deeper level, it can be read 1977 to 1993, the FDA banned “women of child- as gender politics, because gender norms con- bearing potential” from early-phase clinical tri- struct promiscuity as problematic in women, but als.42 The ban’s purpose was to protect fetuses not in men. Mifepristone, similar to hormonal from exposure to investigational drugs that car- contraceptives, raises alarms that it will enable ried unknown risks, especially those that might be women’s promiscuity.36 In contrast, sildenafil teratogenic. While limiting the participation of citrate did not raise alarms about men’s promis- pregnant women in clinical trials may certainly be cuity. Gender politics thus allowed for the rapid an appropriate way to minimize harm to the fetus, approval of sildenafil citrate for the US market.40 the broader ban on women’s inclusion was based In other words, these cases show that gender on the model that women are always potentially politics do not operate only in the assessment of pregnant. Historically, the protection of hypo- risks, benefits, and value of a product designed thetical fetuses took priority over scientific knowl- for women, but also in the review of a therapy for edge about possible sex differences in the safety of Today, companies often explicitly exclude women who are taking hormonal contraceptives from participation in Phase I studies. At times, this prohibition is linked to the companies’ desire to include only healthy subjects who are not taking The first stage of testing new pharmaceuticals in any prescription medications, but frequently there humans is referred to as Phase I clinical trials. These is a specific concern that contraceptives could trials usually commence after sufficient data have change the absorption of the investigational drug been generated from animal studies to indicate to or its adverse-effect profile. Men, in spite of their researchers that an investigational product is rea- naturally occurring hormone cycles, are consid- sonably safe and appears promising as a therapeu- ered to be biologically static, and therefore are tic. The purpose of these studies is to test the safety treated as the norm in science and medicine.43 of the drugs and to establish appropriate doses that Another important contributor to the low par- can be given to humans. Establishing dosage for ticipation of women in Phase I studies is the struc- each drug is usually predicated on the idea that ture of the clinical trials. Because these are safety the dose should be as high as the human body will studies in which the effects in humans are un- tolerate—before the adverse effects become too bur- known, the protocols are predominantly in-patient densome or dangerous for the majority of subjects. confinement studies.44 Although some of these Multiple Phase I trials in which doses are sequen- studies are completed in a weekend, others require tially escalated are necessary for companies to have human subjects to check in to the testing facility enough data to understand the adverse-effect pro- for up to 4-week stints. These studies are simply file of each drug and to settle on the dose of the not compatible with many women’s lives, given drug to be used in the next stage of clinical testing. that women tend to be the primary caretakers of Phase I studies are also known as First-in-Man clinical children and elderly parents. Thus, women may trials. Although this term employs the word “man” be excluded from studies because they cannot in a universal way to indicate the move from animal devote the same amount of time to participation to human testing, its gendered connotation is apt. The vast majority of human subjects in these safety Regardless of the factors creating a gender im- balance in the enrollment rates of men and women in Phase I studies, the effects of it are strik- clinical knowledge that the medical community ing, especially as they reverberate beyond drug has about new drugs is dangerously limited. development to everyday clinical practice.45 For Conducting dosing studies on men skews the instance, women are 1.6 times more likely to devel- established dose of pharmaceuticals to amounts op adverse drug reactions than are men, based on that may not be as well tolerated by women’s bod- how drugs are absorbed, metabolized, and elimi- ies. The issue, however, goes beyond a simple one nated; in addition, women’s reactions tend to be of sex; clinical trials need to include a diverse spec- more severe and serious than are men’s.46,47 Many trum of human participants so that the adverse- researchers attribute these differences to women’s effect profiles of new drugs can be known accord- lower body weight, smaller organ size, and higher ing to sex, age, body weight, and other important factors.49,50 The goal of the FDA should not be to According to the FDA, differences in reactions work with pharmaceutical companies to bring to pharmaceuticals that occur between the sexes their products to market as quickly as possible, but are relatively uncommon, with only 20% of the to provide and enforce policies to ensure that drugs the agency reviews indicating physiological medical providers have a robust knowledge base differences between men and women.1 However, a to draw from when making decisions for their 2001 GAO report criticized the FDA for poor en- forcement, citing evidence that almost 40% of the studies submitted to the FDA fail to reveal the sex Human Papillomavirus Quadrivalent Vaccine of participants and 33% fail to present available HPV is the most common sexually transmitted safety data according to sex.34 The GAO found infection worldwide, contracted by most women this oversight particularly troubling in light of an shortly after the beginning of sexual relations. In earlier investigation which revealed that 8 of the the United States, HPV infects as many as four 10 drugs removed from the market due to safety fifths of women as well as two thirds of men dur- concerns between 1997 and 2000 posed greater ing their lifetime.51 Most cases of HPV are benign for those with fully functioning immune systems, Safety concerns like these emerged only after but both women and men can suffer serious con- the drugs had been approved by the FDA and were sequences of HPV infection. HPV is responsible for widely available to patients. This points to the genital warts and various cancers, most famously, need to more thoroughly understand the effects cervical cancer, but also oral, anal, and penile can- on men and women while these drugs are still cers (Table I).52
under development. Because women are under- The connection between HPV and cervical can- represented in Phase I studies, the scientific and cer was shown in the early 1980s.53 Although Table I. Worldwide cancers attributable to human papillomavirus infection.
cervical cancer is an outcome of HPV, it is by no Table II. Cervical cancer attributable to human papil- means the case that HPV in women inexorably leads to cervical cancer. In fact, healthy women largely fight off HPV as well as the precursors to cervical cancers, lesions known as cervical intra- epithelial neoplasia (CIN) 1, 2, and 3. When the body’s immune system does not fight off the lesions, Pap screening (Papanicolaou smear) can discover them and they can be removed. However, without adequate access to health care, women in developing countries and poor (often minority) that would benefit most from administration of a women in the United States still suffer from cervi- prophylactic HPV vaccine.”56 Even though the cal cancer that could have been prevented by reg- main efficacy studies did not, in this case, include ular screening (Table II).52
boys and men, this Merck researcher also argued Men can also be affected by HPV infection and in favor of vaccinating both girls and boys. The its related ailments. In particular, men who have reasons he provided were that “vaccine coverage sex with men (MSM) suffer disproportionately in girls is going to be incomplete” and “men trans- from anal cancer, which is predominantly caused mit HPV to women.” Drawing on the example of by HPV infection. Indeed, in the United States, the rubella, he suggested that gender-neutral vaccina- rate of anal cancer in MSM rivals the rate of cervi- tion will more effectively reduce the rates of cervi- cal cancer seen in women prior to the introduc- cal cancer. Other researchers have agreed that men tion of routine Pap screening in 1960.54 Currently, should be vaccinated as an additional means to men do not have access to screening tests, and prevent disease in women.57 Yet, this rationale does many are reluctant to utilize available health ser- not take into account the risks that HPV infection vices, which may be amplified in the case of anal poses to men, especially MSM who are at height- examination because of the fear of stigma for ened risk of HPV-related anal cancer. In late 2009, Merck sought and obtained FDA approval to mar- Despite the broader risks of HPV, when Merck & ket the vaccine to males (aged 9–26 years) for the Co., Inc. introduced the HPV quadrivalent vaccine prevention of genital warts caused by HPV; none- to the United States in 2006, it was marketed pri- theless, Merck has not yet promoted its cancer marily as a cervical cancer vaccine for girls and young women.55 The clinical trials did not use Gender politics surrounding the HPV quadriva- cervical cancer as an end point, however, but lent vaccine are most visible when examining how instead used CIN lesions. This end point was it has been marketed as Gardasil* to the US public. approved by the FDA in November 2001 for 2 rea- Avoiding depictions and discussion of sex and sons: not only would demonstrating effectiveness sexual transmission, the vaccine has primarily against cervical cancer require a lengthy trial, but been marketed by mobilizing female empower- it would also mean denying patients the standard ment rhetoric about cancer prevention. In the of care, because CIN lesions are removable.56 advertisements, young women in their twenties Because of the focus on cervical cancer, the main stand confidently, declaring that they want to be efficacy studies included 16- to 26-year-old girls “one less” incident of cervical cancer and explain- and women. The safety studies included both ing “I chose to get vaccinated because…” As is sexes but limited the age of subjects: female par- frequently the case with empowerment rhetoric ticipants were aged 9 to 26 years, whereas male employed in health care contexts, “empower- participants were aged 9 to 15 years.
Merck’s head researcher on the project argued * Trademark: Merck & Co., Inc. (Whitehouse Station, New that these ages were chosen on the basis of “those ment” seems to be achieved solely as the result of ity does not exist in all other parts of the world, as medical choices.58 In this example, the message is Table III shows.64 The sex gap in the United
that girls should protect themselves from cervical States and Europe has made it difficult to recruit cancer with the vaccine—not through sex educa- men as research participants and to perform stud- tion or practicing safer sex. Though it is marketed ies that assess the extent to which the different as a cervical cancer vaccine, it has brewed contro- incidence in men and women is due to biological versy in the United States because the vaccine factors or the gendered nature of the disease.67 cannot be separated from debates about sex educa- Likewise, it has been difficult to prove drug effi- tion,55 and this will likely intensify with the mar- cacy in men without sufficient male clinical trial keting of the vaccine to prevent genital warts in males. While Merck was perhaps aiming to avoid Along with the management of IBS through this controversy, by not tackling it head on the dietary restrictions and stress reduction, several company neglected key issues of public health. drug therapies have been developed that alleviate Not addressing sexual activity means leaving out the symptoms of IBS. Recently, researchers have all the risks of HPV to both male and female part- explored the connections between the brain and ners, regardless of their sexual orientation.
the gut and, following new understandings about the role of serotonin in both, 2 drugs were devel- oped in the 1990s for IBS. First, alosetron was IBS is a chronic condition that causes abdomi- developed for diarrhea-predominant IBS in women. nal pain along with persistent diarrhea, constipa- This is the more common form of IBS in men, but tion, or both. Its symptoms prevent sufferers from the drug was not found to be effective in this sub- everyday activities, as they feel the need to limit group. Alosetron was approved by the FDA in the foods they eat and remain close to a lavatory. February 2000, undeterred by the agency’s aware- Foods that act as triggers include heavy, fatty ness that it may cause ischemic colitis, an enlarge- foods; chocolate; alcohol; and carbonated drinks. ment of the large intestine.68 It was voluntarily In addition, stress can worsen IBS symptoms. Relatively little is known about what causes IBS, but the facts that women’s symptoms worsen dur- Table III. Worldwide prevalence and gender distribution ing menstruation and that men are diagnosed less often than women have led some experts to point to hormonal causes.59–63 In particular, estrogen and progesterone may increase abdominal pain, and testosterone may have a protective effect. This fits with the idea that IBS is a “woman’s disease,” a common misconception that is reinforced by the development and marketing of IBS drugs for women than men in the United States and Western Europe.64 One explanation for this difference lies in the general unwillingness of men to access health services or to let others know they are expe- riencing pain or discomfort.65 However, recent research indicates that men may suffer equally and even access health services for IBS symptoms * Indicates an estimate derived from author’s discussion of overall at the same rate as do women, but do not receive IBS diagnoses from their doctors.66 This sex dispar- withdrawn from the market in November 2000 there was a substantial increase in doctor visits following reports of severe gastrointestinal adverse events, including the death of 5 women taking the In March 2007, less than 5 years after the FDA drug.69 In June 2002, the FDA approved its reentry approved tegaserod, the agency asked Novartis to to the market under restricted conditions. Critics remove the drug from the market. A Swiss govern- have suggested that the FDA’s willingness to return ment meta-analysis of 29 trials had found an in- the drug to the market shows the extent to which creased risk of adverse events—specifically, 13 cases the agency serves the interests of industry.23,69 of heart attacks, stroke, and angina.74 Although In July 2002, the FDA approved another drug tegaserod is a chemical that can bind to receptors for women to treat IBS with constipation. Tegaserod not only in the gut but also in the heart, clinical (Zelnorm®) had been developed by the Swiss phar- trials had not shown any cardiac adverse effects. maceutical company Novartis International AG. In the larger population, however, the drug had The Swiss drug regulatory agency, Swissmedic, had increased the risk of heart attacks. Given the fact approved tegaserod in 2001. Lacking sufficient that it did not consider IBS to be a serious condi- data for its safety and efficacy in men, both Swiss- tion, the FDA decided, along with other regulatory medic and the FDA approved tegaserod for IBS with agencies including Health Canada, that the risk of constipation in women only. Later, the FDA allowed for its extension to men for the related condition of chronic constipation. This was based on 2 clinical trials in which 86% and 90% of the respective study Sex and gender play a role in every stage of phar- populations were female.70 Notably, some questions maceutical regulation, from the design of clinical were raised during FDA hearings about the appro- trials and the approval of new drugs to advertising priateness of approving tegaserod for men with and postmarketing surveillance. However, regula- chronic constipation, given the paucity of male tory agencies pay insufficient attention to mean- clinical trial subjects and concern about extrapolat- ingful differences between women and men in ing study results from females to males.70,71 terms of both sex and gender. This disregard, in After the US approval of tegaserod, Novartis our view, perpetuates inequalities by neglecting began an intensive marketing campaign that fea- drug safety problems that predominate in one sex tured women’s bare abdomens with words written and by allowing misleading drug marketing that in black marker such as “Yes, there’s help,” “I’m reinforces gender stereotypes.34,75 Clinical trials, feeling better,” and “Ask your doctor.” The adver- for example, frequently lack an even composition tising thus steered clear of the unsavory aspects of of men and women. The first stage of testing drugs the condition by focusing instead on attractive on humans, Phase I, is described as “First-in-Man,” young female bodies. Although IBS with chronic a phrase that is often literally true. Although some constipation is common among all age groups— steps have been taken to include women, most and can worsen during menopause—these adver- drugs are tested for safety primarily on men, which tisements featured attractive young bodies of thin, is problematic because women often experience primarily white, women in their twenties. In addi- more severe adverse effects and may require lower tion, newspaper advertisements were designed doses. Pharmaceutical companies should be required that included disease promotion campaigns for to include representative populations in Phase I IBS itself, which gave information that “her pain studies so that the drugs that are brought to mar- and suffering are over … in just three days,” and ket are safer for the patients consuming them.
thus overstated the efficacy of tegaserod.72 Because In contrast to most Phase I trials, the examples of limitations to FDA enforcement of advertising of the HPV quadrivalent vaccine and tegaserod regulations, however, the warning letter was issued show that some clinical trials for effectiveness 3-1/2 months after the appearance of the adver- (known as Phase III) use few male subjects. In the tisements it referenced. During these 3 months, case of the HPV vaccine, studies initially focused on cervical cancer precursors rather than the range politics in sales and marketing (Table IV). Ideally,
of conditions that HPV causes. For marketing rea- this should include a critical understanding of the sons, one particular cancer in women took prece- way that pharmaceutical companies use gender to dence over other HPV-caused diseases, which are construct disease and disease markets. As the less prevalent in men and women but nonetheless Sarafem example at the outset of this article shows, significant.52 The preponderance of data about the the current system of pharmaceutical regulation drug’s effects on women and the virtual absence of allows for companies to create new brands with- data about effects on men hinder public health ef- out inventing new products.19,23 Critical attention forts to tackle HPV. Similarly, tegaserod was approved to gender could help to reveal contestations be- for IBS in women only. In this case, the rationale hind disease categories like PMDD and strengthen was not that men are unaffected by IBS or that the the FDA’s ability to evaluate advertising.
drug was ineffective in men, but simply that it was Fundamental challenges remain, however. In- difficult to find male research subjects.71 Although adequacies with current drug regulation restrict the drug was subsequently approved for chronic the possibilities of making pharmaceutical over- constipation in both sexes, it is interesting to note sight fair and effective for everyone. FDA oversight that there was discussion within the FDA regarding of pharmaceutical advertising has little value the applicability of women’s trial results to men. because of the delay between the start of a market- This indicates a double standard that is operating, ing campaign and the sending of a warning letter. wherein regulators do not question the generaliz- Current standards for proof of safety and efficacy ability of data derived from male participants but neglect to compare investigational products against question the applicability of data from women to the standard of care, which means that new drugs men. To enable both men and women to benefit may be no more effective and possibly more harm- safely from new pharmaceuticals, standards need to ful than the existing treatment options. Both be applied symmetrically so that one sex is not con- women’s and men’s health are more likely to be sidered the norm to which the other is held.
endangered when regulatory bodies fail to engage Beyond representation in clinical trials, regula- these issues. Meaningful change, therefore, requires tory institutions need to attend to sex and gender that government agencies prioritize public health Table IV. Attending to sex and gender at every stage.
Actors Who Need to Pay Attention to Sex and Gender Together, these actors must pay attention to sex and gender in the design and implementation of each stage of the pharmaceutical life cycle, as well as to the policies governing each stage. Crucially, these policies must also be enforced.
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Address correspondence to: Jill A. Fisher, PhD, Center for Biomedical Ethics & Society, Vanderbilt University,
2525 West End Avenue, Suite 400, Nashville, TN 37203. E-mail: jill.fisher@Vanderbilt.Edu

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Consulta pÚblica nº 30, de 19 de agosto de 2010

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