Current Commentary
Underrepresentation of Women in Clinical Trials Why Gynecologic Oncologists Are Worried Marcela G. del Carmen,
MD, MPH,
and Laurel W. Rice,
In gynecologic oncology, significant advances with improved patient outcomes have clearly and thankfully resulted from randomized clinical trials. The recent restructuring of cooperative groups and decreased funding for phase III clinical trials have unintentionally resulted in a 90% reduction of available trials and accrual in gynecologic oncology. This Commentary reviews the history of the underrepresentation of women in clinical trials, highlighting the challenges that threaten the viability of gynecologic oncology clinical research, resulting in a decreased likelihood of improving the survival of women with gynecologic cancer. We suggest an opportunity for partnering with the U.S. government and the private sector to enhance research funding opportunities while increasing advocacy efforts to reinvigorate our clinical trials platform. (Obstet Gynecol 2015;125:616–9) DOI: 10.1097/AOG.0000000000000695
L
evel 1 evidence, randomized clinical trials are the gold standard by which we care for and advise our patients. The Gynecologic Oncology Group (GOG), which was established in 1965, has been the bedrock on which research in our field has been conducted. Data generated from several randomized clinical trials executed through the GOG have resulted in improved patient survival. Examples of these advances include From the Division of Gynecologic Oncology, Vincent Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and the Department of Obstetrics and Gynecology, University of Wisconsin Hospital and Clinics, Madison, Wisconsin. Corresponding author: Marcela G. del Carmen, MD, MPH, Division of Gynecologic Oncology, Vincent Obstetrics and Gynecology, Massachusetts General Hospital, 55 Fruit Street, Yawkey 9 E, Boston, MA 02114; e-mail: [email protected]. Financial Disclosure The authors did not report any potential conflicts of interest. © 2015 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0029-7844/15
616
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MD
the addition of chemotherapy to radiation in the treatment of patients with cervical cancer and the adoption of intraperitoneal chemotherapy in ovarian cancer, both of which have resulted in two National Cancer Institute (NCI) clinical alerts.1–6 With the recent changes in the NCI’s clinical trials infrastructure, combined with commentary from Dr. Francis Collins and more (see below), there is mounting evidence regarding the disproportionately low allocation of resources for enrolling women in clinical trials in general and in gynecologic oncology trials specifically. Historically, clinical trials were carried out in men only. The argument for doing so included the rationale that male-only studies were simpler and less expensive to conduct.7 Investigators were also reticent to include women of childbearing age, given the potential risk of harming a fetus.7 As a result, women were excluded from many vitally important clinical trials.7 In the Harvard Physicians’ Health Study, evaluating the effects of aspirin on cardiovascular disease and published in 1989, 22,071 male and 0 female physicians were enrolled.8 In the Multiple Risk Factor Intervention Trial—evaluating the relationship between blood pressure, cholesterol, tobacco use, and coronary artery disease (and published in 1982)—12,866 men and 0 women were enrolled.9 The Baltimore Longitudinal Study of Aging, conducted from 1958 to 1975 and published in 1986, included men only.10 Most notably (and most interestingly), the first study to evaluate the therapeutic role of estrogen in cardiovascular disease prevention was conducted in men only.11 The counterpoint is the Nurses’ Health Study, with more than 87,000 female nurses, which evaluated the use of low-dose aspirin and risk of myocardial infarction in women.12 However, unlike the Physicians’ Health Study previously described, the Nurses’ Health Study was an observational investigation and not a randomized trial.12 A plethora of data support that the extrapolation of information from male-only trials to the diagnosis,
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
prevention, and treatment of these conditions in women results in both their undertreatment and overtreatment.7 Medications potentially therapeutic in women may be discarded from studies prematurely if the trials include only male participants.13,14 Sex differences in drug metabolism exist, such as the elimination of acetaminophen, which women metabolize at 60% the rate of that noted for men.13 Women are at greater risk of adverse events associated with medication use, with an example being erythromycininduced Torsades de Pointes, which occurs two to three times more commonly in women than in men.14 Causality for these observations remains elusive and may be explained, at least in part, by sexrelated differences in metabolism and immunology and by changes associated with the menstrual cycle, pregnancy, and menopause.15,16 Socially and politically, the period between 1973 and 1993 saw the insurgence of a women’s health movement focused on the principle that biomedical research must equally meet the needs of men and women and that studies including women must expand beyond reproduction.7,17 The pressure calling for reform in biomedical research prompted the Assistant Secretary of Health to establish the Public Health Task Force on Women’s Health Issues. In 1985, the Task Force issued a report stating, “The historical lack of research focus on women’s health concerns has compromised the quality of health information available to women, as well as the health care they receive,” and that “Biomedical and behavioral research be expanded to ensure emphasis on conditions and diseases unique to, or more prevalent, in women in all age groups.”18 In 1987, subsequent to the report, the National Institutes of Health (NIH) established a policy urging applicants for research funding to include women in clinical trials, which was published in the NIH Guide to Grants and Contracts. It became evident that these guidelines were not being met. Consequently, with urging from the Society of Women’s Health Research (founded in 1990), the Congressional Caucus on Women’s Health Issues requested that the Government Accountability Office investigate matters relevant to the inclusion of women in clinical trials. The Office of Research on Women’s Health was established in 1990 and was charged with developing opportunities for women engaged in biomedical professions and ensuring that NIH-initiated and -funded research adequately cover disorders affecting women.7 In response to the report from the Government Accountability Office, the NIH required that any special exclusions be considered in the peer-reviewed process. In 1993, Congress passed the National Institutes of Health Revitalization Act.7,19
VOL. 125, NO. 3, MARCH 2015
This Act required that women and minorities be included in all NIH-supported research and specifically in phase III clinical trials in numbers appropriate to allow adequate data analysis. The Act also specified that cost was not an acceptable reason to exclude these groups and provided special support for programs focusing on the recruitment and retention of women and minorities as participants in clinical studies. The current state of representation of women in biomedical research remains a problem: women are inadequately represented. Among published non–sexspecific studies supported by the NIH between 1993 and 1998, approximately one fifth of these studies failed to include women as research participants.20 Of trials that included women, only one quarter to one third of the studies analyzed the data by sex.20 In a review of clinical trial data submitted to the U.S. Food and Drug Administration for New Molecular Entities for adult, non–sex-specific indications (January 2006 and December 2007), 34% of trials had only male participants and 66% had both men and women. In terms of total participants, only 31% (3,106/10,134) were women.15 Importantly, safety and tolerability testing above the highest approved dose occurred in only 43% of trials, of which only 32% of participants were women.15 Furthermore the 5-year trend of total enrollment for domestic extramural NIH clinical research for fiscal years 2008–2012 is notable for 7,618,658 women out of a total of 11,797,605 enrollees in 2008 and 6,173,108 women out of a total of 11,066,707 enrollees in 2012.21 These figures represent a 6.2% decrease in the total number of enrollees and an astounding concomitant 19% decrease in the number of women.21 In 2010, the Institute of Medicine reported that the design, analysis, and reporting of clinical research presently limits researchers’ ability to perform statistically significant subgroup analysis to determine whether outcomes vary between men and women.20 In Nature, May 15, 2014, Dr. Francis Collins, Director of the NIH, and Dr. Janine Clayton, Director of the Office of Research on Women’s Health, summarized and clearly acknowledged the overwhelming body of literature supporting that sexbased considerations and analyses are neglected in cell and animal research.22 As gynecologic oncologists, 100% of the patients we care for are women; thus, this underrepresentation of women in clinical trials as well as in cellular and animal research is of utmost importance. This challenge extends to other specialties in our field outside of gynecologic oncology. Funding cuts in reproductive medicine are evident in the continuous decrease in the number of sites in the U54 Specialized Cooperative
del Carmen and Rice
Women in Clinical Trials
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
617
Center Programs for Infertility and Reproduction Research. Historically, this program funded a maximum of 14 centers, but presently it is charged to fund one less program per year, with the ultimate goal of funding only nine programs. This funding cut has been instituted despite the review committee’s recommendation to not only continue but also expand the program. Additional supportive evidence includes the reduction of funding for the Women’s Reproductive Health Research Career Development Program. This vital training program was established to fund recent graduates of obstetrics and gynecology residency programs in basic, translational, and clinical research through a K12 mechanism and is being cut to support 14 sites with two positions each from previous funding of 18 sites with three positions each. Objective analysis shows that, in the past two decades, women have fared quite well in cancer clinical trial enrollment, primarily because of high enrollment of women in breast cancer trials. However, in gynecologic oncology, we are not experiencing the same stable or increased funding, which may in part be a result of the fact that gynecologic cancers are less common than breast cancer and have more limited access to in vivo laboratory research. This translates to a weakened position for the new NCItargeted therapies and science-driven trials. The GOG has a 50-year history of generating trials in partnership with the NCI’s Cancer Therapy Evaluation Program, resulting in the design and execution of practice-changing studies.23 But as the NIH budget stagnates at best, the battle for dollars escalates. Restructuring of cooperative groups, including Disease Site Steering Committees such as the Gynecologic Cancer Steering Committee and the National Cancer Trials Network, has occurred. Further reorganization has resulted in the formation of NRG Oncology, a nonprofit corporation founded in 2012, consolidating three adult NCI clinical cooperative groups, namely the GOG, the National Surgical Adjuvant Breast and Bowel Project, and the Radiation Therapy Oncology Group. The contraction of the clinical trial portfolio secondary to static NCI funding coupled with the increased expense of clinical trials has led to a concerted effort by the Cancer Therapy Evaluation Program and the steering committee to reduce clinical trial enrollment. Unintentionally, this restructuring, combined with a decline in enrollment of patients in phase III clinical trials, has significantly diminished our ability to conduct the clinical trials that have the greatest opportunity for improving the lives of women with gynecologic malignancies. Figure 1 shows the Cancer Therapy Evaluation Program–sponsored GOG phase
618
del Carmen and Rice
Women in Clinical Trials
Fig. 1. Histogram of cancer therapy evaluation program–sponsored Gynecologic Oncology Group phase I, II, III trials, 2009–2013. Data from: Gynecologic Oncology Group. GOG and CTEP trials [white paper]. Available at: http://www.cancerletter.com/downloads/ 20140221_1/download. Retrieved December 2, 2014. del Carmen. Women in Clinical Trials. Obstet Gynecol 2015.
I, II, and III trials from 2009 to 2013.23 Between 2010 and 2014, there was a 56% reduction in the National Cancer Trials Network enrollment in phase III clinical trials. For fiscal year 2011, the NCI reported its expenditure for clinical trials to be $878.4 million, or 17.4% of its $5.1 billion budget. In the past, the GOG has been able to open 10–12 trials per year, with the potential to accrue an estimated 3,000 patients annually.23 However, there has been a sharp decline in sponsored trial activation for the GOG by the Cancer Therapy Evaluation Program over the past 6 years.23 In fact, in 2013, only one trial opening was approved, with a potential to accrue 148 participants.23 The Cancer Therapy Evaluation Program phase III trial accrual in early 2014 was reduced to 201 patients annually, in contrast to an average of 2,190 participants in 2010 and 2011, representing a 90% reduction in phase III trial accrual.23 This massive reduction in trial availability and accrual may have a calamitous and potentially irremediable effect on the future of clinical trials in gynecologic cancers.23 The gynecologic oncology clinical trial infrastructure is vulnerable. Although we acknowledge the need for restructuring of the cooperative group system into the National Cancer Trial Network, it is important to recognize that less-common tumors, such as gynecologic cancers, are susceptible to underfunding. Our charge is to secure allocation of funding and enrollment numbers that will allow us to maintain a nationwide infrastructure and facilitate the design of more exploratory trials. Possible mechanisms to effect this change include a strong partnership with industry through the Gynecologic Oncology Group Foundation. We must also continue to work with the Cancer
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Therapy Evaluation Program to identify mechanisms that will increase and broaden the gynecologic oncology trials portfolio. Stronger international collaboration is important with both of these options. With the recognition that basic science research in gynecologic oncology lags in comparison with other malignancies, such as breast, lung, colon and prostate, another possible solution would include stronger investment in translational research and consolidation of efforts to support novel trial design. Given that gynecologic cancers are uncommon, securing the future of biomedical research in this field also will require a cooperative group infrastructure to effectively run phase II translational trials. Because these trials currently are not being funded by the Cancer Therapy Evaluation Program, single institution R01 funding mechanisms should be considered. A hybrid model, in which the Cancer Therapy Evaluation Program expands its interest in working with industry outside of full Cooperative Research and Development Agreements, may afford companies the option to conduct low-cost, innovative, exploratory trials. The Cancer Therapy Evaluation Program also could consider supporting other types of trials outside of those evaluating targeted therapies, including surgical, radiation, and imaging studies. There is work to be done in increasing the enrollment of women in clinical trials across all disciplines in medicine. Investing in research that is focused on gynecologic oncology is one of many approaches that would place this mission on the proper trajectory. As health care providers committed and dedicated to the advancement of the health and wellbeing of women, the responsibility rests with all of us. REFERENCES
5. Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 2006;354:34–43. 6. National Cancer Institute. Clinical advisory: NCI issues clinical announcement for preferred method of treatment for advanced ovarian cancer. Available at: http://www.nlm.nih.gov/databases/alerts/ovarian_ip_chemo.html. Retrieved November 25, 2014. 7. Schiebinger L. Women’s health and clinical trials. J Clin Invest 2003;112:973–77. 8. Steering Committee of the Physicians’ Health Study Research Group. Final report on the aspirin component of the ongoing Physicians’ Health Study. N Engl J Med 1989;321:129–35. 9. Multiple Risk Factor Intervention Trial Research Group. Multiple risk factor intervention trial. Risk factor changes and mortality results. JAMA 1982;248:1465–77. 10. Rossman I. Normal human aging: the Baltimore longitudinal study of aging JAMA 1986;255:960–6. 11. Cauley JA, Gutai JP, Kuller LH, Dai WS. Usefulness of sex steroid hormone levels in predicting coronary artery disease in men. Am J Cardiol 1987;60:771–7. 12. Stampfer MJ, Colditz GA, Willett WC, Manson JE, Rosner B, Speizer FE, et al. Postmenopausal estrogen therapy and cardiovascular disease. Ten-year follow-up from the nurses’ health study. N Engl J Med 1991;325:756–62. 13. Merkatz RB, Temple R, Sobel S, Feiden K, Kessler DA; Working Group on Women in Clinical Trials. Women in clinical trials of new drugs. N Engl J Med 1993;329:292–6. 14. Drici MD, Knollmann BC, Wang WX, Woosley RL. Cardiac actions of erythromycin: influence of female sex. JAMA 1998; 280:1774–6. 15. Pinnow E, Pellavi S, Parekh A, Gevorkian N, Uhl K. Increasing participation of women in early phase clinical trials approved by the FDA. Women’s Health Issues 2009;19:89–93. 16. Harris RZ, Benet LZ, Schwartz JB. Gender effects in pharmacokinetics and pharmacodynamics. Drugs 1995;50:222–39. 17. Institute of Medicine. Exploring the biological contributions to human health: does sex matter? Washington, DC: National Academies Press; 2001. 18. Women’s health. Report of the public health service task force on women’s health issues. Public Health Rep 1985; 1001:73–106.
1. Whitney CW, Sause W, Bundy BN, Malfetano JH, Hannigan EV, Fowler WC Jr, et al. Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol 1999;17:1339–48.
19. US Congress. National Institutes of Health Revitalization Act of 1993: act to amend the Public Health Service Act to revise and extend the programs of the National Institutes of Health, and for other purposes. Public Law 103–43. Washington, DC: US Congress; 1993.
2. Rose PG, Bundy BN, Watkins EB, Thigpen JT, Deppe G, Maiman MA, et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 1999;340:1144–53.
21. Department of Health and Human Services, National Institutes of Health. Monitoring adherence to the NIH policy on the inclusion of women and minorities as subjects in clinical research. Comprehensive report: tracking of clinical research as reported in fiscal year 2011 and fiscal year 2012. Available at: http://orwh.od.nih.gov/research/inclusion/pdf/InclusionComprehensiveReport-FY-2011-2012.pdf. Retrieved August 16, 2014.
3. Keys HM, Bundy BN, Stehman FB, Muderspach LI, Chafe WE, Suggs CL III, et al. Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 1999;340:1154–61. 4. National Cancer Institute. NCI issues clinical announcement on cervical cancer: chemotherapy plus radiation improves survival. Available at: http://www.nih.gov/news/pr/feb99/nci-22. htm. Retrieved November 25, 2014.
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20. IOM. Women’s health research: progress, pitfalls and promise. Washington, DC: National Academies Press; 2010.
22. Clayton JA, Collins FS. Policy: NIH to balance sex in cell and animal studies. Nature 2014;509:282–3. 23. Gynecologic Oncology Group. GOG and CTEP trials [white paper]. Available at: http://www.cancerletter.com/downloads/ 20140221_1/download. Retrieved August 16, 2014.
del Carmen and Rice
Women in Clinical Trials
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
619
Underrepresentation of Women in Clinical Trials Why Gynecologic Oncologists Are Worried Marcela G. del Carmen,
MD, MPH,
and Laurel W. Rice,
In gynecologic oncology, significant advances with improved patient outcomes have clearly and thankfully resulted from randomized clinical trials. The recent restructuring of cooperative groups and decreased funding for phase III clinical trials have unintentionally resulted in a 90% reduction of available trials and accrual in gynecologic oncology. This Commentary reviews the history of the underrepresentation of women in clinical trials, highlighting the challenges that threaten the viability of gynecologic oncology clinical research, resulting in a decreased likelihood of improving the survival of women with gynecologic cancer. We suggest an opportunity for partnering with the U.S. government and the private sector to enhance research funding opportunities while increasing advocacy efforts to reinvigorate our clinical trials platform. (Obstet Gynecol 2015;125:616–9) DOI: 10.1097/AOG.0000000000000695
L
evel 1 evidence, randomized clinical trials are the gold standard by which we care for and advise our patients. The Gynecologic Oncology Group (GOG), which was established in 1965, has been the bedrock on which research in our field has been conducted. Data generated from several randomized clinical trials executed through the GOG have resulted in improved patient survival. Examples of these advances include From the Division of Gynecologic Oncology, Vincent Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and the Department of Obstetrics and Gynecology, University of Wisconsin Hospital and Clinics, Madison, Wisconsin. Corresponding author: Marcela G. del Carmen, MD, MPH, Division of Gynecologic Oncology, Vincent Obstetrics and Gynecology, Massachusetts General Hospital, 55 Fruit Street, Yawkey 9 E, Boston, MA 02114; e-mail: [email protected]. Financial Disclosure The authors did not report any potential conflicts of interest. © 2015 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0029-7844/15
616
VOL. 125, NO. 3, MARCH 2015
MD
the addition of chemotherapy to radiation in the treatment of patients with cervical cancer and the adoption of intraperitoneal chemotherapy in ovarian cancer, both of which have resulted in two National Cancer Institute (NCI) clinical alerts.1–6 With the recent changes in the NCI’s clinical trials infrastructure, combined with commentary from Dr. Francis Collins and more (see below), there is mounting evidence regarding the disproportionately low allocation of resources for enrolling women in clinical trials in general and in gynecologic oncology trials specifically. Historically, clinical trials were carried out in men only. The argument for doing so included the rationale that male-only studies were simpler and less expensive to conduct.7 Investigators were also reticent to include women of childbearing age, given the potential risk of harming a fetus.7 As a result, women were excluded from many vitally important clinical trials.7 In the Harvard Physicians’ Health Study, evaluating the effects of aspirin on cardiovascular disease and published in 1989, 22,071 male and 0 female physicians were enrolled.8 In the Multiple Risk Factor Intervention Trial—evaluating the relationship between blood pressure, cholesterol, tobacco use, and coronary artery disease (and published in 1982)—12,866 men and 0 women were enrolled.9 The Baltimore Longitudinal Study of Aging, conducted from 1958 to 1975 and published in 1986, included men only.10 Most notably (and most interestingly), the first study to evaluate the therapeutic role of estrogen in cardiovascular disease prevention was conducted in men only.11 The counterpoint is the Nurses’ Health Study, with more than 87,000 female nurses, which evaluated the use of low-dose aspirin and risk of myocardial infarction in women.12 However, unlike the Physicians’ Health Study previously described, the Nurses’ Health Study was an observational investigation and not a randomized trial.12 A plethora of data support that the extrapolation of information from male-only trials to the diagnosis,
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
prevention, and treatment of these conditions in women results in both their undertreatment and overtreatment.7 Medications potentially therapeutic in women may be discarded from studies prematurely if the trials include only male participants.13,14 Sex differences in drug metabolism exist, such as the elimination of acetaminophen, which women metabolize at 60% the rate of that noted for men.13 Women are at greater risk of adverse events associated with medication use, with an example being erythromycininduced Torsades de Pointes, which occurs two to three times more commonly in women than in men.14 Causality for these observations remains elusive and may be explained, at least in part, by sexrelated differences in metabolism and immunology and by changes associated with the menstrual cycle, pregnancy, and menopause.15,16 Socially and politically, the period between 1973 and 1993 saw the insurgence of a women’s health movement focused on the principle that biomedical research must equally meet the needs of men and women and that studies including women must expand beyond reproduction.7,17 The pressure calling for reform in biomedical research prompted the Assistant Secretary of Health to establish the Public Health Task Force on Women’s Health Issues. In 1985, the Task Force issued a report stating, “The historical lack of research focus on women’s health concerns has compromised the quality of health information available to women, as well as the health care they receive,” and that “Biomedical and behavioral research be expanded to ensure emphasis on conditions and diseases unique to, or more prevalent, in women in all age groups.”18 In 1987, subsequent to the report, the National Institutes of Health (NIH) established a policy urging applicants for research funding to include women in clinical trials, which was published in the NIH Guide to Grants and Contracts. It became evident that these guidelines were not being met. Consequently, with urging from the Society of Women’s Health Research (founded in 1990), the Congressional Caucus on Women’s Health Issues requested that the Government Accountability Office investigate matters relevant to the inclusion of women in clinical trials. The Office of Research on Women’s Health was established in 1990 and was charged with developing opportunities for women engaged in biomedical professions and ensuring that NIH-initiated and -funded research adequately cover disorders affecting women.7 In response to the report from the Government Accountability Office, the NIH required that any special exclusions be considered in the peer-reviewed process. In 1993, Congress passed the National Institutes of Health Revitalization Act.7,19
VOL. 125, NO. 3, MARCH 2015
This Act required that women and minorities be included in all NIH-supported research and specifically in phase III clinical trials in numbers appropriate to allow adequate data analysis. The Act also specified that cost was not an acceptable reason to exclude these groups and provided special support for programs focusing on the recruitment and retention of women and minorities as participants in clinical studies. The current state of representation of women in biomedical research remains a problem: women are inadequately represented. Among published non–sexspecific studies supported by the NIH between 1993 and 1998, approximately one fifth of these studies failed to include women as research participants.20 Of trials that included women, only one quarter to one third of the studies analyzed the data by sex.20 In a review of clinical trial data submitted to the U.S. Food and Drug Administration for New Molecular Entities for adult, non–sex-specific indications (January 2006 and December 2007), 34% of trials had only male participants and 66% had both men and women. In terms of total participants, only 31% (3,106/10,134) were women.15 Importantly, safety and tolerability testing above the highest approved dose occurred in only 43% of trials, of which only 32% of participants were women.15 Furthermore the 5-year trend of total enrollment for domestic extramural NIH clinical research for fiscal years 2008–2012 is notable for 7,618,658 women out of a total of 11,797,605 enrollees in 2008 and 6,173,108 women out of a total of 11,066,707 enrollees in 2012.21 These figures represent a 6.2% decrease in the total number of enrollees and an astounding concomitant 19% decrease in the number of women.21 In 2010, the Institute of Medicine reported that the design, analysis, and reporting of clinical research presently limits researchers’ ability to perform statistically significant subgroup analysis to determine whether outcomes vary between men and women.20 In Nature, May 15, 2014, Dr. Francis Collins, Director of the NIH, and Dr. Janine Clayton, Director of the Office of Research on Women’s Health, summarized and clearly acknowledged the overwhelming body of literature supporting that sexbased considerations and analyses are neglected in cell and animal research.22 As gynecologic oncologists, 100% of the patients we care for are women; thus, this underrepresentation of women in clinical trials as well as in cellular and animal research is of utmost importance. This challenge extends to other specialties in our field outside of gynecologic oncology. Funding cuts in reproductive medicine are evident in the continuous decrease in the number of sites in the U54 Specialized Cooperative
del Carmen and Rice
Women in Clinical Trials
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
617
Center Programs for Infertility and Reproduction Research. Historically, this program funded a maximum of 14 centers, but presently it is charged to fund one less program per year, with the ultimate goal of funding only nine programs. This funding cut has been instituted despite the review committee’s recommendation to not only continue but also expand the program. Additional supportive evidence includes the reduction of funding for the Women’s Reproductive Health Research Career Development Program. This vital training program was established to fund recent graduates of obstetrics and gynecology residency programs in basic, translational, and clinical research through a K12 mechanism and is being cut to support 14 sites with two positions each from previous funding of 18 sites with three positions each. Objective analysis shows that, in the past two decades, women have fared quite well in cancer clinical trial enrollment, primarily because of high enrollment of women in breast cancer trials. However, in gynecologic oncology, we are not experiencing the same stable or increased funding, which may in part be a result of the fact that gynecologic cancers are less common than breast cancer and have more limited access to in vivo laboratory research. This translates to a weakened position for the new NCItargeted therapies and science-driven trials. The GOG has a 50-year history of generating trials in partnership with the NCI’s Cancer Therapy Evaluation Program, resulting in the design and execution of practice-changing studies.23 But as the NIH budget stagnates at best, the battle for dollars escalates. Restructuring of cooperative groups, including Disease Site Steering Committees such as the Gynecologic Cancer Steering Committee and the National Cancer Trials Network, has occurred. Further reorganization has resulted in the formation of NRG Oncology, a nonprofit corporation founded in 2012, consolidating three adult NCI clinical cooperative groups, namely the GOG, the National Surgical Adjuvant Breast and Bowel Project, and the Radiation Therapy Oncology Group. The contraction of the clinical trial portfolio secondary to static NCI funding coupled with the increased expense of clinical trials has led to a concerted effort by the Cancer Therapy Evaluation Program and the steering committee to reduce clinical trial enrollment. Unintentionally, this restructuring, combined with a decline in enrollment of patients in phase III clinical trials, has significantly diminished our ability to conduct the clinical trials that have the greatest opportunity for improving the lives of women with gynecologic malignancies. Figure 1 shows the Cancer Therapy Evaluation Program–sponsored GOG phase
618
del Carmen and Rice
Women in Clinical Trials
Fig. 1. Histogram of cancer therapy evaluation program–sponsored Gynecologic Oncology Group phase I, II, III trials, 2009–2013. Data from: Gynecologic Oncology Group. GOG and CTEP trials [white paper]. Available at: http://www.cancerletter.com/downloads/ 20140221_1/download. Retrieved December 2, 2014. del Carmen. Women in Clinical Trials. Obstet Gynecol 2015.
I, II, and III trials from 2009 to 2013.23 Between 2010 and 2014, there was a 56% reduction in the National Cancer Trials Network enrollment in phase III clinical trials. For fiscal year 2011, the NCI reported its expenditure for clinical trials to be $878.4 million, or 17.4% of its $5.1 billion budget. In the past, the GOG has been able to open 10–12 trials per year, with the potential to accrue an estimated 3,000 patients annually.23 However, there has been a sharp decline in sponsored trial activation for the GOG by the Cancer Therapy Evaluation Program over the past 6 years.23 In fact, in 2013, only one trial opening was approved, with a potential to accrue 148 participants.23 The Cancer Therapy Evaluation Program phase III trial accrual in early 2014 was reduced to 201 patients annually, in contrast to an average of 2,190 participants in 2010 and 2011, representing a 90% reduction in phase III trial accrual.23 This massive reduction in trial availability and accrual may have a calamitous and potentially irremediable effect on the future of clinical trials in gynecologic cancers.23 The gynecologic oncology clinical trial infrastructure is vulnerable. Although we acknowledge the need for restructuring of the cooperative group system into the National Cancer Trial Network, it is important to recognize that less-common tumors, such as gynecologic cancers, are susceptible to underfunding. Our charge is to secure allocation of funding and enrollment numbers that will allow us to maintain a nationwide infrastructure and facilitate the design of more exploratory trials. Possible mechanisms to effect this change include a strong partnership with industry through the Gynecologic Oncology Group Foundation. We must also continue to work with the Cancer
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Therapy Evaluation Program to identify mechanisms that will increase and broaden the gynecologic oncology trials portfolio. Stronger international collaboration is important with both of these options. With the recognition that basic science research in gynecologic oncology lags in comparison with other malignancies, such as breast, lung, colon and prostate, another possible solution would include stronger investment in translational research and consolidation of efforts to support novel trial design. Given that gynecologic cancers are uncommon, securing the future of biomedical research in this field also will require a cooperative group infrastructure to effectively run phase II translational trials. Because these trials currently are not being funded by the Cancer Therapy Evaluation Program, single institution R01 funding mechanisms should be considered. A hybrid model, in which the Cancer Therapy Evaluation Program expands its interest in working with industry outside of full Cooperative Research and Development Agreements, may afford companies the option to conduct low-cost, innovative, exploratory trials. The Cancer Therapy Evaluation Program also could consider supporting other types of trials outside of those evaluating targeted therapies, including surgical, radiation, and imaging studies. There is work to be done in increasing the enrollment of women in clinical trials across all disciplines in medicine. Investing in research that is focused on gynecologic oncology is one of many approaches that would place this mission on the proper trajectory. As health care providers committed and dedicated to the advancement of the health and wellbeing of women, the responsibility rests with all of us. REFERENCES
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