The objective of the meeting between US Food and Drug Administration (FDA) Office of Women’s Health (OWH) and the Centre for Gender Medicine at Karolinska Institutet (KI), Sweden, was to discuss each institution’s perspective on and approach to addressing women’s health issues. The presentations at this meeting are summarized in this report. They were related to approaches to research in sex and gender differences and education both in the US and Sweden. The challenges facing this field today were discussed as well as potential solutions and collaboration.

Karolinska Institutet Presentations:

Gender Medicine in Europe

Professor. Karin Schenck-Gustafsson reported on gender medicine (GM) in Europe and the Swedish approach to this matter over the past decade.

The Centre for Gender Medicine at Karolinska Institutet was established in 2001 to promote public and medical professional awareness of the impact of gender and sex on health and disease by providing high-class education and funding frontline research in the field.¹ The Center addresses differences between men’s and women’s health and disease through research and education. Since its initiation the center has focused on educating physicians, scientists and health professionals in this promising field to help address challenges in this arena. Under Dr. Schenck-Gustafsson’s direction, the Center for Gender Medicine has awarded 15 PhDs in gender medicine, published over 300 articles on the subject matter and released a textbook “Handbook on Clinical Gender Medicine² with outstanding editors and authors from across the globe. In addition, the Center has built a network of more than 500 persons throughout the world. The Center has focused on the following research areas: cardiovascular disease; steroid hormones and metabolism; neuropsychiatry and stress research; inflammation and autoimmune disease; and public health issues. Further, the center offers educational programs in Gender Medicine including a Master’s in GM, a PhD course in GM, continuing education for teachers and post-graduate education and lectures for the public. Dr. Schenck-Gustafsson emphasized that in the future the medical/research community must be accepting of GM as a specialty and thus pressure will be put on authorities at all levels to advance the Center’s efforts. In addition, she recommended that Societies for GM to be established to help move the field forward. She concluded with focusing on the regulatory challenges facing the field, identifying problem with post-marketing surveillance and suggesting the US Food and Drug Administration and the Swedish Medical Products Agency working together to confront emerging challenges.

Swedish Healthcare and the Potentials for Epidemiological Research

Dr. Björn Wettermark gave an overview of the Swedish healthcare system and the potentials to study utilization, effectiveness and safety of medicines. Briefly, the Swedish health care system is financed by taxes, organized in independent counties and divides its responsibilities at the local, regional and national levels. Traditionally, the healthcare system has primarily been publicly owned and dominated by hospitals. In addition, the Sweden has established a sophisticated reimbursement system for medicines as well as a strong clinical research community. The last decade, the system has undergone many pharmaceutical reforms which have resulted in a rather rational use of drugs and control of drug spending.³ There is also a great potential to monitor drug utilization and outcomes in Nordic countries. Data sources for drug utilization studies include the drug industry, wholesalers, claims/reimbursement databases, pharmacy databases, disease based registers and collection of data directly from patients. The government has established several national registries for monitoring health and medical services with each person having a unique Personal Identification Number (PIN).⁴ Nordic Health data registers include: cancer register; medical birth and congenital malformations register; hospital patient register; cause-of-death register; and prescribed/dispensed drug register.⁵ The speaker noted several advantages of the registers including reduced time and cost of research given the registers have been established, large sample size, long term and complete follow-up with patients, high validity of data and independent collection of data. However, problems with registers include poor quality of certain data, limited clinical data, the temptation of researchers to perform post hoc analyses and potential lack of information on confounders. Further, the Swedish health care system has not established national registers including all devices but there is a national pacemaker/ICD register as well as a national PCI/CABG register. There are also specific registers on devices used in orthopedic surgery. Other therapies such as over-the-counter drug products are available on an aggregate level only. Overall, he suggested that the Swedish health care register system provides valuable data that may be relevant in advancing gender based science and healthcare.

Decision Support Systems for Drug Prescribing

Dr. Mia von Euler’s presentation focused on rational drug use, stating the importance of patients receiving appropriate medication to treat their medical condition based on individual requirements (e.g. age, condition, co-morbidity, metabolic function, other drugs, pregnancy, breastfeeding, gender). This is a challenge for the individual physician. She stated that approximately 90% of all prescriptions in Stockholm are electronic thereby facilitate the possibly of introducing electronic decision-support systems via computerized medical records. There are a number of support systems developed in Sweden. One of them is Janus toolbar, including alert warnings for drug-drug interactions, drug use in pregnancy and breastfeeding.⁶ However, there is no information on gender aspects important to take into consideration when prescribing drugs. The aim of the Swedish SALAR project is to increase the quality of drug treatment and decrease adverse drug reaction (ADR) in men and women. The web-based support tool known as Janus toolbar will be integrated in electronic health records and connect to high quality data sources as well as drug identification which would lead to relevant alerts and warnings to In the future, the group aims to create a database named the Gender Button to evaluate the clinical aspects, clinical consequence and clinical recommendations achieved from development of this project. The working group thinks that ADRs occurring because of gender differences in doses, or drug-drug interactions may also be prevented by this platform. Ideally, information available in the decision support system would include metabolic differences, other drugs used, drug use in pregnancy and drug use in breastfeeding as well as individual conditions. However, this system will not capture underuse of drugs, which is a challenge facing the field worldwide.^7,8

It was noted that the two institutions may possibly collaborate in developing standard operating procedures, building a proper data bank, and providing expertise in various specialty areas.

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U.S. Food and Drug Administration Presentations:

The Office of Women’s Health: A Brief Overview

Marsha Henderson, FDA Assistant Commissioner for Women’s Health gave a brief overview of women’s health at the agency. The Office of Women’s Health at the FDA was established in 1994 to protect and advance the health of women through policy, science, and outreach as well as to advocate for inclusion of women in clinical trials and analysis of sex/gender effects.⁹ The OWH partners with several internal and external offices and participates in numerous activities including sex/gender research, health professional training, scientific workshops and health education and outreach. The Office was established following a report that women were not adequately represented in clinical studies and that data is often not analyzed for sex/gender differences. Overall, the Office aims to ensure that all research initiatives have a regulatory impact and are focused on understanding sex differences to drug response differences in men and women, inclusion of women and safety outcomes in clinical trials and data standards. The office is also making transformational changes in its approach to women’s health through research efforts such as breast cancer imaging, product labeling changes; identification of sex differences in drug induced QT prolongation, an award-winning consumer education program and a comprehensive Pregnancy Registry Website.

In conclusion, she suggested that the office is uniquely positioned to aid in meeting the challenges facing the women’s health community and is enthusiastic about potential partnership with the Karolinska Institutet.

The Sentinel Initiative

Dr. Patrick Archdeacon (Office of Medical Policy, Center for Drug Evaluation and Research, FDA) briefly discussed the Sentinel Initiative, which resulted as an outcome of the FDA Amendments Act of 2007 to leverage health-related electronic data across a variety of sources. Briefly, the Sentinel Initiative is a national electronic system that will transform the FDA’s ability to track the safety of drugs, biologics, and medical devices within the market.¹⁰ The aim of the initiative was to establish a post market risk identification and analysis system to link and analyze safety data from multiple sources with a goal of enlisting 100,000,000 patients by July 1, 2012. The system would independently collect data from Federal health-related electronic systems and private sector health-related electronic data systems. The initiative would help improve FDA’s capability to identify and investigate safety issues in near real time and enhance its ability to evaluate safety issues that are not easily investigated with the passive surveillance systems in place. The Sentinel Initiative is intended to augment, not replace, a comprehensive surveillance program by adding active surveillance to a system which already includes drug utilization data, pharmaco-epidemiologic studies, passive surveillance as well as external health care databases. He noted that FDA and its partners have developed the Mini-Sentinel pilot program. The Mini-Sentinel Distributed Database (MSDD) is owned by FDA and operated by its contractor (Harvard-Pilgrim), but leverages primary data that remain entirely in the control of its partner organizations from within the private healthcare sector. The MSDD describes populations with well-defined person-time for which medically-attended events are known utilizing both administrative and clinical data. Through the MSDD, Mini-Sentinel has access to data from over 126 million individuals including 345 million person-years of observation time. He concluded by stating that in the future the Sentinel will be a long-term, complex initiative which aims to complement other Health and Human Services initiatives that use distributed systems for comparative effectiveness and quality assurance.

FDA Driving Biomedical Product Innovation- A Critical Role for Regulatory Science

Dr. Vicki Seyfert-Margolis (Office of the Commissioner, FDA) discussed the need for advancement of regulatory science both internally and externally. She stated that FDA-regulated products account for approximately 20-25 cents of every consumer dollar spent in the U.S. demonstrating its impact on the economy. The agency recently released a strategic plan for advancing regulatory science at FDA¹¹ which focuses on the following priority areas: toxicology modernization to enhance safety; innovation in clinical evaluation and personalized medicine; improvement in product manufacturing and quality; FDA readiness to evaluate Emerging Technologies; harnessing diverse data through Information Sciences to improve health outcomes; prevention focused Food Safety system; Medical Countermeasures development to protect US and global health security; and strengthening Social and Behavioral Science to help consumers and professional make informed decisions. To help achieve the objectives outlined in the strategic plan the agency has recently funded two awards to Georgetown University and the University of Maryland to develop Centers of Excellence in Regulatory Science and Innovation. In addition, FDA has made advancements in addressing immediate concerns by rebuilding its small business outreach services, building infrastructure to drive personalized medicine, creating an expedited drug development pathway, harnessing potential of data mining and information sharing as well as streamlining and reforming numerous FDA regulations. She stated that the FDA’s role is to bring together stakeholders to identify and overcome the challenges ahead, implement reforms that adapt to the changing scientific and technological landscape and assure modern, streamline regulatory pathways are present.

“HoW” to Improve the Health of Women

Kathryn O’Callaghan and Nada Hanafi discussed the Center for Devices and Radiological Health newly established Health of Women (HoW) Program. The mission of the HoW Program is two-fold: to improve the availability and consistency of sex-specific information for the safe and effective use of medical devices in women, and to improve the health of women as a special/priority population by targeting resources and fostering the development of innovative technology and clinical study paradigms to address identified gaps and unmet needs. The major priority activities for this program include 1) recruitment and retention strategies, 2) data analysis and communication of sex-specific findings, 3) gap analysis and coordinated research within priority product areas of known sex differences or unmet women’s health needs. At present, there is a new FDA Draft Guidance for Evaluation of Sex Differences in Medical Device Clinical Studies which aims to achieve representative enrollment of women in clinical trials, obtain sex-specific data and achieve transparent reporting of sex-specific findings to the public. The intended impact of these policies is to better communicate the balance of risks and benefits to the patient and physician, identify questions for further study, and demonstrate that covariates of sex and other demographics should be considered during the design stage.

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References:

1 Karolinska Institutet Center for Gender Medicine

2 “Handbook of Clinical Gender Medicine” editors, Karin Schenck-Gustafsson,Paula de Cola, Donald Pfaff, David Pisetsky, Karger AG 2012,ISBN 978-3-8055-9929-0, e-ISBN 978-3-8055-9930-6

3 Godman B, Wettermark B, Hoffmann M, Andersson K, Haycox A, Gustafsson LL. Swedish experience in ambulatory care with multifaceted national and regional drug reforms and initiatives: global relevance. Expert Review of Pharmacoeconomics and Outcomes Research 2009;9:65-83

4 Ludvigsson JF, Otterblad-Olausson P, Pettersson BU, Ekbom A. The Swedish personal identity number: possibilities and pitfalls in healthcare and medical research. Eur J Epidemiol 2009;24:659

5 Furu K, Wettermark B, Andersen M, Martikainen JE, Almarsdottir AB, Sørensen HT. The Nordic Countries as a Cohort for Pharmacoepidemiological Research. Basic Clin Pharmacol Toxicol. 2010;106:86-94

6 Eiermann B, Bastholm-Rahmner P, Korkmaz S, Lilja B, Veg A, Wettermark B, Gustafsson LL. Knowledge databases for clinical decision support in drug prescribing- development, quality assurance, management, integration, implementation and evaluation of clinical value. Chapter in Clinical Decision Support, Vienna 2009

7 Loikas D, Wettermark B, Von Euler M, Bergman U, Weitoft GR, Schenck-Gustafsson K. Big gender differences in drug utilization. The underlying disease is an insufficient explanation according to a systematic analysis]. [Article in Swedish] Swedish Medical J, 2011 Oct 5-11; 108(40):1957-62.

8 Loikas D, Wettermark B, Von Euler M, Bergman U, Weitoft GR, Schenck-Gustafsson K, Differences in drug utilization between men and women: a cross sectional database analysis of dispensed drugs in Sweden, In review

9 The Office of Women’s Health, Food and Drug Administration

10 The Sentinel Initiative

11 Advancing Regulatory Science at FDA: Strategic Plan