Sex, clinical trials and medicines regulation part II

Drug Approval Regulation in Canada and USA

Since the thalidomide tragedy in the late1950s, there has been a reluctance to include women of childbearing age in clinical trials. However, this fear cannot be used as an excuse to not include females in clinical trials, and, with proper care and regulation, increased female participation has been reached. The United States adopted regulation early on to increase the participation of women, while a new regulation in Europe is going to improve this as well. Here follows an overview of the issue in Canada and in the USA. The third part of this series will deal with new regulation in Europe.

Health Canada Guidance Document                                                                                     

In 2013, Health Canada issued a Guidance document to address the under representation of women in clinical trials. Health Canada argue that “analysis of clinical trial data by sex may identify clinically relevant sex differences in therapeutic response and, as a result, minimize the risks, maximize benefits and promote the optimal use of therapeutic products in both women and men” (Health Canada, 2013). The Guidance document also includes pregnant and breastfeeding women. As well as this, it recommends that, if data from early phase trials do not indicate potential sex-related differences, it cannot be assumed that clinically relevant differences do not exist. The Guidance document therefore recommends that the statistical section of the study protocol for Phase III trials include pre-specific plans for asserting sex related differences.

The US Food and Drug Administration

The US has been on the forefront of developing policies for including population groups such as women and minorities in biomedical research and clinical studies. Policy drivers have been Congress, the National Institutes of Health (NIH) with its Office of Research on Women’s (ORWH), as well as the Food and Drug Administration (FDA) and its Office of Women’s Health (OWH), which was established by Congressional mandate in 1994. As far back as 1993, the NIH addressed the exclusion of women from biomedical and clinical studies through the NIH Revitalisation Act that called for women and minorities to be included in all human subject research in adequate numbers to allow for valid analyses in phase III clinical trials. The NIH explicitly stated that cost was not an acceptable reason for excluding women and minorities.

FDA has produced guidelines to ensure that women will be appropriately represented (FDA, 1993). While not mandatory, it amended the previous FDA policy of excluding most women of childbearing age to participate in early phases of clinical trials. The FDA’s Office of Women’s Health advocates for the participation of women in clinical trials, and for sex, gender and subpopulation analysis. It protects and supports the health of women through policy and science. The FDA requires sponsors to include a fair representation of both sexes as participants in clinical trials so that clinically related differences in response can be detected. The guidelines state that sponsors should collect gender-related data during research and development, and analyse the data for gender effects in addition to the other variables of age and race.

FDA Safety and Innovation Act

The FDA Action Plan to Enhance the Collection and Availability of Demographic Subgroup Data (2014) sets out important steps for making clinical trial data across the demographic spectrum of sex, race/ethnicity, and age more transparent and publicly available. It reflects the FDA’s commitment to encourage the inclusion and greater representation of a diverse patient population in biomedical research leading to the development of medicinal products to meet the health needs of patients. The Action Plan asks for subgroup data to be analysed, thus ensuring the safety and effectiveness of the medicinal product in a wider population. The Action Plan includes 27 items for improving the completeness and quality of demographic subgroup data collection, reporting and analysis (quality); identifying barriers to subgroup enrolment in clinical trials and employing strategies to encourage greater participation (participation); and, making demographic subgroup data more available and transparent (transparency).

FDA Drug Trial Snapshots

This is a new programme initiated under the 27-step Action Plan to make demographic subgroup data more widely available. A sample of Snapshots for recently approved products was posted on the FDA website for comment. Starting in 2015, based on the feedback received, FDA has posted a Snapshot for every new medicinal product approved. The Snapshots provide easy to understand information at a glance: including demographic breakdown by sex, age, and ethnicity and providing efficacy and safety results sorted demographically. However, FDA cautions that “conclusions regarding how effective and safe a drug is among different sex, race, and age groups cannot always be made, often because the numbers of patients in some groups are too limited to allow for meaningful comparisons to other groups and to the overall results” (FDA, 2016). This statement points out one of the major challenges that still need to be tackled.

Food and Drug Administration (1993) Guidance for Industry, Rockville, MD: US Department of Health and Human Services, Food and Drug Administration.
Food and Drug Administration (2014) FDA Action Plan to Enhance the Collection and Availability of Demographic Subgroup Data, Silver Spring MD: Food and Drug Administration.
Food and Drug Administration (2015) ‘FDA Drug Trials Snapshots’ [online] available: [accessed 29 October 2016].
Health Canada (2013) ‘Guidance Document: Considerations for Inclusion of Women in Clinical Trials and Analysis of Sex Differences’ [online] available: [accessed 29 October 2016].
National Institutes of Health Revitalization Act of 1993, Public Law 103-43, s. Subtitle B—Clinical Research Equity Regarding Women and Minorities, Washington D.C.: US Government.

MMLAP and other EU Projects

Health system analysis to support capacity development in response to the threat of pandemic influenza in Asia
Making society an active participant in water adaptation to global change
Public Participation in Developing a Common Framework for Assessment and Management of Sustainable Innovation
Engaging all of Europe in shaping a desirable and sustainable future
Expect the unexpected and know how to respond
Driving innovation in crisis management for European resilience
Effective communication in outbreak management: development of an evidence-based tool for Europe
Solutions to improve CBRNe resilience
Network for Communicable Disease Control in Southern Europe and Mediterranean Countries
Developing the framework for an epidemic forecast infrastructure
Strengthening of the national surveillance system for communicable diseases
Surveillance of vaccine preventable hepatitis
European monitoring of excess mortality for public health action
European network for highly infectious disease
Dedicated surveillance network for surveillance and control of vaccine preventable diseases in the EU
Modelling the spread of pandemic influenza and strategies for its containment and mitigation
Cost-effectiveness assessment of european influenza human pandemic alert and response strategies
Bridging the gap between science, stakeholders and policy makers
Promotion of immunization for health professionals in Europe
Towards inclusive research programming for sustainable food innovations
Addressing chronic diseases and healthy ageing across the life cycle
Medical ecosystem – personalized event-based surveillance
Studying the many and varied economic, social, legal and ethical aspects of the recent developments on the Internet, and their consequences for the individual and society at large
Get involved in the responsible marine research and innovation
Knowledge-based policy-making on issues involving science, technology and innovation, mainly based upon the practices in Parliamentary Technology Assessment
Assessment of the current pandemic preparedness and response tools, systems and practice at national, EU and global level in priority areas
Analysis of innovative public engagement tools and instruments for dynamic governance in the field of Science in Society
Public Engagement with Research And Research Engagement with Society
Computing Veracity – the Fourth Challenge of Big Data
Providing infrastructure, co-ordination and integration of existing clinical research networks on epidemics and pandemics
Promote vaccinations among migrant population in Europe
Creating mechanisms for effectively tackling the scientific and technology related challenges faced by society
Improve the quality of indoor air, keeping it free from radon
Improving respect of ethics principles and laws in research and innovation, in line with the evolution of technologies and societal concerns
Investigating how cities in the West securitise against global pandemics
Creating a structured dialogue and mutual learning with citizens and urban actors by setting up National Networks in 10 countries across Europe
Identifying how children can be change agents in the Science and Society relationship
Establishing an open dialogue between stakeholders concerning synthetic biology’s potential benefits and risks
Transparent communication in Epidemics: Learning Lessons from experience, delivering effective Messages, providing Evidence