Collecting Sex, Gender, or Both in Clinical Trials?

In the latest issue of JAMA, Clayton and Tannenbaum published an article titled “Reporting Sex, Gender, or Both in Clinical Research?” and raised an interesting question whether or not we should collect the sex, gender, or both in clinical trials.

Coincidently, just last month (Oct 26, 2016), FDA published a guidance for industry and FDA staff “Collection of Race and Ethnicity Data in Clinical Trials”. While the guidance is about the data collection for race and ethnicity, it mentions in several places both the sex and gender. On page 3 of the guidance, it uses the footnote to explain the differences between terms sex and gender.

The terms sex and gender have been used interchangeably in some FDA documents. However, according to a 2001 consensus report from the Institute of Medicine (Institute of Medicine, Committee on Understanding the Biology of Sex and Gender Differences. Exploring the Biological Contributions to Human Health: Does Sex Matter?, National Academy of Sciences, 2001), the terms have distinct definitions which should be used consistently to describe research results. Sex refers to the classification of living things, generally as male or female according to their reproductive organs and functions assigned by chromosomal complement. Gender refers to a person’s self-representation as male or female, or how that person is responded to by social institutions based on the individual’s gender presentation (perhaps Masculine vs. feminine). Gender is rooted in biology, and shaped by environment and experience. Because of underlying differences in the statutes and regulations referenced in this policy, the terms “gender” and “sex” have both been used in this document in accordance with the source material referenced.

Institute of Medicine, Committee on Understanding the Biology of Sex and Gender Differences. Exploring the Biological Contributions to Human Health: Does Sex Matter?, (National Academy of Sciences, 2001) has formally provided the different definitions for term ‘Sex’ and ‘Gender’ and consider the ‘Sex’ and ‘Gender’ having different meaning.

Prior to IOM report, the definitions for sex and gender have already been proposed in ICH guideline "Sex-related Considerations in the Conduct of Clinical Trials". ICH guideline has the following about the sex and gender.

The terms sex and gender have been used interchangeably in many of the previously adopted ICH guidelines. In recognition of currently accepted distinction between these concepts, the term sex will be used in all new and revised ICH guidelines to denote the biogenetic differences that distinguish males and females. While different definitions may exist respecting the term gender, it is understood that gender generally refers the array of socially constructed roles and relationships, behaviours and values that society ascribes to two sexes on a differentiated basis. 

It makes sense to differentiate the concept of sex and gender. With the definition above proposed by IOM, whether or not collecting sex or gender or both may depend on the indication or disease area. As recommended by Clayton and Tannenbaum in their JAMA article, we should “use the terms sex

When reporting biological factors and gender when reporting gender identity or psychosocial or cultural factors”. In psychology / psychiatry field, collecting the data on gender may be equally important to collecting the data on sex.

I believe that the current standard practice in clinical trial is still to use the terms sex and gender interchangeably. The case report form for demographic collects sex or gender (with male or female as categories), but not both. Providing different definitions for term ‘sex’ and ‘gender’ is driven by the potential participation of transgender subjects in clinical trials. Instead of collecting both sex and gender information, it might be easier just to add two additional categories to the data collection:

Sex/Gender: Male, Female, Transgender (Male to Female), Transgender (Female to Male).

FDA and EMA have both published the guidelines to encourage the data collection about demographic information and to perform subgroup analysis based on the demographic information. The sex or gender is big part of it. It is critical to have women subjects represented in the clinical trials. It is critical to collect and analyze the data to determine if there is sex difference in treatment effect. In some therapeutic areas, clinical trials may need to collect both the sex and gender information.    

• FDA Is Committed to Determining Sex Differences in How Drugs Work
• FDA Report Collection, Analysis, and Availability of Demographic Subgroup Data for FDA-Approved Medical Products August 2013
• FDA Action plan to enhance the collection and availability of demographic subgroup data
• FDA - Understanding Sex Differences
• FDA - Participation of Females in Clinical Trials and Gender Analysis of Data in Biologic Product Applications
• ICH – Gender Considerations in the Conduct of Clinical Trials
• EMA Guideline on the Investigation of Subgroups in Confirmatory Clinical Trials
• EUGenMed Roadmap for Including Sex & Gender in Biomedical & Public Health Research
• EMA - Sex and Gender in EU Regulatory Practice