Next Section: Roadmap Vision
- Office of Women's Health Research Program
- The Importance of Women's Health Research
- Developing the Roadmap
- Definition of Woman
The U.S. Food and Drug Administration (FDA) is a science-based, regulatory agency with the core mission14 of protecting the public health. FDA plays a significant role in the lives of most Americans. FDA-regulated products touch the lives of most American every day. In fact, estimates are that FDA-regulated products account for at least 20 cents of every dollar spent by American consumers each year.15
Regulatory science, the science of developing new tools, standards, and approaches to assess the safety, efficacy, quality, and performance of FDA-regulated products,16 underpins every regulatory decision FDA makes. The research under way at FDA helps FDA scientists assess the toxicity or the safety, efficacy, quality, and performance of the medical and other products FDA regulates. This research also contributes to advances in science and technology in general and promotes innovation in medical product development and food and cosmetic safety. FDA’s research also helps alert the Agency to potential safety issues, like product contamination and other problems that may become apparent only after a product enters the marketplace.
FDA has a long history of expanding its understanding of the possible different effects of the products it regulates on men and women. The analysis of such possible differences is a routine part of FDA’s product review process. For example, FDA has long expected medical product developers to include animals17 of both sexes when performing preclinical studies of candidate drugs or biological products. Developers must document study results, including on age, sex, the source of the animals being used, and the immediate source of any cell lines and their origins. FDA recommendations vary depending on product area. For example, in nonclinical studies (i.e., not in humans) of medical devices, the difference between species often has a greater influence than the difference between sexes.
It is also important to look for sex differences during clinical testing (i.e., in humans). FDA regulations18 require the presentation in marketing applications of demographic data (e.g., on age, sex and race) to help identify important information about possible differences among demographic subgroups in the safety or effectiveness of drugs. Developers must analyze safety and effectiveness data, including pooled data for any clinically relevant and statistically significant sex differences, for these demographic subgroups and must include the information in their new drug or biologic applications. FDA has also issued guidance to industry describing how to plan for and analyze clinical data to identify sex-related differences for medical devices. 19 During FDA review of a marketing application, FDA carefully determines whether the available clinical data can be generalized and applied to subgroups. FDA may require additional studies to address areas of concern identified in pre- or postmarket clinical data.
FDA’s Office of Women’s Health (OWH) was established in 1994 to provide leadership on women’s health issues within FDA. OWH’s stated mission is to help protect and advance the health of women through policy, science, and outreach; advocate for inclusion of women in clinical trials and analysis of sex effect; and increase scientific knowledge through advanced professional training/education in subpopulation analysis. 20
In 1994, OWH established a research and development program to undertake the following:
- Advance the evaluation of sex-based differences in the safety and efficacy of FDA-regulated products
- Conduct research on health conditions and diseases that solely or disproportionately affect women
- Track the participation of women and special populations in clinical studies and improve demographic subset analyses
- Advance scientific knowledge through advanced professional training and education in subpopulation analysis and women’s health
As of 2015, OWH had funded 340 research projects totaling approximately $35 million. OWH-funded projects, which are typically carried out by FDA centers, have addressed health issues affecting women across their lifespan. Projects have ranged from investigating listeria in pregnancy and cosmetic safety to the study of, sexually transmitted infections, cardiovascular disease, breast cancer, reproductive health, endocrine and neurological disorders, and psychiatric disorders, among other conditions. 21 This research has contributed to safety labeling changes for medical products, new guidance for industry on product development, data standardization for vaccine clinical data, standards for evaluation of tampons and condoms, and evidence-based support for consumer decision about products recommended for use by pregnant women (e.g., the risks and benefits of fish consumption).22 OWH-funded research has also served as the foundation for the development and expansion of other women’s health research activities, including, for example, the National Center for Toxicological Research’s annual Women’s Health Research Program.23
OWH supports FDA’s public health and consumer protection mission using multiple approaches. OWH may also lead or coordinate research, policy development, and educational and communication initiatives addressing women’s health when they involve multiple FDA centers and/or external collaborators. As described in the box below in more detail, the Office of Women’s Health Research Program supports a variety of activities, including, for example, intramural research grants, FDA research program collaborations, external research collaborations, workshops and training, and OWH conducted research. As described in the box below in more detail, the Office of Women’s Health Research Program supports a variety of activities, including, for example, intramural research grants, FDA research program collaborations, external research collaborations, workshops and training, and OWH conducted research.
Intramural Research Grants
Competitive Grants: Peer-reviewed grants are awarded to FDA-scientists who respond to an annual call for proposals from OWH.
Special Funding Initiatives: Special projects are awarded to FDA scientists outside of the competitive process to respond to emerging and pressing women’s health issues. These funds can also be used to support workshops, surveys, and focus group testing.
FDA Research Program Collaborations
FDA product centers and offices directly support scientific research in the form of grants, cooperative agreements, or contracts. OWH collaborates with other FDA research programs, like the Critical Path Initiative, to better integrate women’s health research questions into their research activities.
External Research Collaborations
These may involve special projects conducted with other governmental agencies and other external partners to help FDA leverage all available technologies, expertise, and resources when addressing complex research questions.
OWH Workshops and Training
Scientific workshops and trainings/curriculum development for health professionals are designed to advance the understanding of women‘s health and sex-related differences.
OWH Conducted Research
OWH projects have been launched to assess the level of participation by women and analysis of outcomes by sex in clinical trials in support of product applications submitted to FDA.
The OWH Research and Development Program plays an integral role in promoting sound policies and regulations by supporting research projects, workshops, and training to help FDA answer regulatory questions related to women’s health.
Women’s health research is critically important. We know that disease sometimes manifests differently in women than in men; sometimes women also respond differently to FDA-regulated products. A number of factors can influence these differences. Intrinsic factors (e.g., genetics, hormones, body size, sex-specific physiology), extrinsic factors (e.g., diet, sociocultural issues, environment), phenotypic differences, 24 or interactions among these factors can play an important role in how women respond to therapies. Characteristics associated with female sex (e.g., size, age, co-morbidities, past pregnancies) may be associated with differences in the safety or effectiveness of a particular medical product.
Because these differences in health, disease, and treatment response can occur throughout a woman’s life span―and may be substantial, depending on her stage of life―a deeper analysis is needed of how regulated products work in diverse populations of women. For example, fluctuations of hormones across the lifespan can affect clinical outcomes: the loss of estrogen due to oophorectomy; menopause, whether natural or premature, contributes to loss of bone mineral density, which can lead to osteoporosis, increased risk of fracture, and increased morbidity and mortality. Thus, it is important to understand whether and how hormonal changes affect product performance at the onset of puberty, during the menstrual cycle, during pregnancy, and during the transition from pre-menopause, to peri-menopause, to post-menopause. We must improve our understanding of how to identify and interpret sex differences in addition to understanding how these differences might affect treatment. This is especially important, given the many evolving new technologies and scientific fields, such as nanotechnology; pharmacogenomics; stem cells; advanced manufacturing techniques, like 3-D printing 25; and novel imaging techniques and methods used to improve diagnosis. Advances in our understanding in these areas will contribute to FDA’s ability to carefully evaluate the many innovative therapeutic products in the development pipeline.
New clinical trial and study designs, such as adaptive and enrichment studies, could help ensure effective use of small samples and sub-population analyses. New methods, processes, and tools, including modeling (e.g., in vitro and computational modeling) and other novel technologies, can help evaluate medical device designs, predict toxicity, or predict the safety and efficacy of FDA-regulated products and guide medication dosing for women. Biomarkers, surrogate endpoints, 26 patient reported outcomes, 27 and other tools are increasingly being used during medical product development and in the clinic to help understand disease, therapy, and patient response to therapy. Advances in the science of biomarkers could help improve our understanding of the molecular underpinnings of disease in women and provide the data necessary to evaluate the safety and effectiveness of medical products, leading to advances in personalized, or precision, medicine. 28
It is also critical to gain a better understanding of how to incorporate and interpret data, including data from clinical trials carried out in other countries, which may not be consistent with U.S. demographic profiles, during premarket review and during surveillance once therapies are on the market and being used by women.
Last but not least, the information gained from this research must be clear and readily available to multiple diverse subpopulations of women to help them and their health care professionals make informed choices about the regulated products available to them. Social science research can help identify and evaluate methods for eliciting patient perspectives on disease, treatment options, and effects of treatment and for delivering information to women and determining how individual factors like sex, age, culture, and health literacy might affect consumer understanding of product labeling and other FDA communications about regulated products.
FDA is interested in any patient or population characteristics that might affect the course of a disease or condition or the toxicity, safety, or effectiveness of an FDA-regulated product available to women. The goal is not just to identify that differences exist from one subpopulation to the next. The goal is to determine when identified differences have clinically meaningful 29 effects on patient health. This information can then be used to guide clinical decisions about the optimum course of action and inform the development of better diagnostic and therapeutic products for all subpopulations of women.
By promoting collaborative research in mission critical areas, developing new tools, applying this new knowledge during FDA’s review process, and strategically coordinating the findings so that they inform regulatory and policy decisions, FDA will be better positioned to foster the advancement of innovative products that promote and protect the health of all Americans.
In 2013, OWH launched a process to develop a new research strategy, a roadmap that could build on knowledge gained from previously funded research and assist OWH in coordinating future health research activities with other FDA research programs and with external partners. As part of the process of developing the Roadmap, OWH evaluated its existing research portfolio to determine regulatory impact. OWH performed a gap analysis to identify critical women’s health issues that have not been addressed and conducted discussions with representatives from FDA’s centers and offices to identify additional women’s health research priorities and related policy questions. Based on information gained through this process, OWH developed a list of proposed research areas considered to be high priority. The list was then vetted within FDA. Because we view the Roadmap as a living document, we will revise it over time, as needed.
While identifying these priority research areas, OWH decided to focus on areas where advancements around FDA-regulated products used by women would be directly relevant to FDA as it makes regulatory decisions related to the toxicity or the safety, efficacy, and security of FDA-regulated products in women.30 Future research projects supported by OWH through the Roadmap must align with FDA’s priorities and strategic goals 31 and with the expectations laid out in the Roadmap. Projects should focus on gaps in knowledge about FDA-regulated products used by women and directly inform FDA’s scientific and regulatory decisions related to these products.
OWH’s goal in developing the Roadmap was to provide a science-based framework within which to build women’s health science into all of FDA’s research activities. Using the Roadmap, OWH can make funding decisions that are aligned with FDA’s research priorities. The Roadmap will ensure the efficient use of FDA resources while addressing the women’s health research questions that are especially important to FDA’s regulatory decision making. The Roadmap will also serve as a catalyst for future collaborations intended to help protect and promote the health of women through advancements in policy and science and through outreach. The Roadmap is considered such an important component in FDA’s current activities related to optimizing women’s health that it was designated a key FDA commitment in FDA’s August 2014 Action Plan to Enhance the Collection and Availability of Demographic Subgroup Data. 32
It is important to note that although there are differences among FDA centers on the definition of adult, for the purposes of the research that will be supported through the Roadmap, we generally define an adult as an individual 17 years or older. Additionally, FDA acknowledges the complex and evolving research needs related to transgender populations. OWH intends to include transgender-related research as it relates to FDA regulatory products.
Next Section: Roadmap Vision
14 See http://www.fda.gov/downloads/aboutfda/reportsmanualsforms/reports/budgetreports/ucm298331.pdf .
15 See Executive Summary of FDA's Strategic Plan for Advancing Regulatory Science Accessed August 2015.
16 The entire Strategic Plan for Advancing Regulatory Science is available at http://www.fda.gov/scienceresearch/specialtopics/regulatoryscience/ucm267719.htm. Accessed June 2015.
17 Note that FDA is committed to reducing the number of animals used in testing, or eliminating their use all together to the extent possible. One tool that is helping achieve that goal is computer simulation modeling.
18 See 21 Code of Federal Regulations 314.50.
19 See, for example, FDA guidance Evaluation of Sex-Specific Data in Medical Device Clinical Studies. Accessed August 2015.
20 Find more information on the OWH. Accessed March 2015.
21 The extent of OWH funding of initiatives related to tobacco products is limited, to some extent, by authorities laid out in statutory language authorizing the Center for Tobacco Products (CTP). CTP funds research related to its statutory authority. Information on CTP research activities, including funding underway and funding opportunities, is available on the CTP website. Accessed September 2015.
22 Obias-Manno D, Scott PE, Kaczmarczyk J, et al. The Food and Drug Administration, Office of Women’s Health: Impact of Science on Regulatory Policy. J Womens Health 2007 July-Aug; 16(6)807-17, available at http://www.ncbi.nlm.nih.gov/pubmed/17678451. Accessed March 2015. Note: a second article is in development describing more recent contributions of OWH-funded research.
23 This event is a result of OWH funding. NCTR scientists and other experts present scientific findings on women’s health.
24 Phenotypic differences are the observable physical or biochemical characteristics of an organism, as determined by both genetic makeup and environmental influences.
25 3-D manufacturing/ 3-D printing also known as additive manufacturing involves building an object by printing something layer by layer.
26 Section 4 of this report discusses biomarkers in more detail. Generally speaking, a biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention (Strimbu K and Tavel JA. 2010. What are biomarkers? Curr Opin HIV AIDS 2010; 5: pp. 463–466). A surrogate endpoint is a biomarker that predicts the clinical benefit (or harm, or lack of benefit) of a treatment based on epidemiologic, therapeutic, pathophysiologic or other scientific evidence (Feigin A. 2004. Evidence from Biomarkers and Surrogate Endpoints. NeuroRX 2004: 1 (3): pp. 323-330). A clinical endpoint is a characteristic or variable that reflects how a patient feels, functions, or survives (Sullivan EJ. Clinical Trial Endpoints). Available at: http://www.fda.gov/downloads/Training/ClinicalInvestigatorTrainingCourse/UCM283378.pdf. Accessed March 2015.
27 A patient reported outcome (PRO) is any report of the status of a patient’s health condition that comes directly from the patient, without interpretation of the patient’s response by a clinician or anyone else. In clinical trials, a PRO instrument can be used to measure the effect of a medical intervention on a symptom or group of symptoms, on effects on a particular function or group of functions, or on a group of symptoms or functions shown to measure the severity of a health condition. PRO instruments have proved useful in assessing medical product labeling claims. See, for example, FDA guidance, available at http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm193282.pdf. Accessed June 2015.
28 Also known as individualized treatment, or targeted therapy, precision medicine makes use of blood tests, images of the body, or other technologies to measure individual factors called biomarkers. These biomarkers can then be used to determine who is most likely to benefit from a treatment, who is at higher risk of a side effect, or who needs a different dose. For more, see http://blogs.fda.gov/fdavoice/index.php/2015/03/fda-continues-to-lead-in-precision-medicine/. Accessed September 2015.
29 The definition of clinically meaningful can vary depending on the disease or condition being considered, the therapy under consideration, and the goal of therapy. Generally, however, it can be understood to mean a measurable medical or statistical benefit to a patient or subgroup, respectively, in a given situation.
30 Many important women’s health issues exist that are not directly related to regulatory decision making. To address these issues, OWH is committed to building collaborations or lending technical expertise in capacities other than direct OWH funding.
31 For example, FDA issued its Strategic Plan for Advancing Regulatory Science. Accessed June 2015.
32 View the 2014 Action Plan. Accessed September 2015. The Action Plan was provided for in Section 907 of the Food and Drug Administration Safety and Innovation Act (FDASIA).