Bridging the Translational Gap: A Review of ‘Navigating the Paradigm Shift of Sex-Inclusive Preclinical Research’

Over the past few decades, the biomedical research community has undergone a crucial, though long-overdue, transformation: the push towards sex-inclusive research. The article titled "Navigating the Paradigm Shift of Sex-Inclusive Preclinical Research", published in Communications Biology and archived in the NIH's PubMed Central, provides an insightful overview of this shift, detailing the history, current challenges, and future directions of integrating sex as a biological variable in preclinical studies. 

Background: Male Bias in Preclinical Science

Historically, biomedical research has disproportionately relied on male animals in laboratory studies. This male-centric approach was largely driven by the assumption that female physiology, particularly hormonal fluctuations related to the oestrous cycle, would introduce unwanted variability and complicate data analysis. However, this exclusion has had significant consequences.

By excluding females, scientists have missed critical insights into sex-specific mechanisms of disease and treatment response (see our blog on gender disparities in neuroscience). This oversight has contributed to inadequate drug efficacy and safety for women, highlighting a major flaw in the foundations of evidence-based medicine.

The Shift Toward Inclusion

The article emphasises that the push for sex-inclusive research has gained momentum in recent years, due in large part to advocacy by scientists, healthcare professionals, and policy makers who recognise the scientific and ethical necessity of inclusive research practices.

A key milestone was reached in 2016 when the U.S. National Institutes of Health (NIH) implemented a policy requiring all NIH-funded researchers to factor sex as a biological variable (SABV) into their experimental designs, analyses, and reporting. This policy marked a turning point, shifting sex inclusion from "nice-to-have" to a core requirement. 

Biological Rationale: Sex Matters

What makes this topic so critical is that sex differences are not limited to reproductive anatomy and hormone levels - they extend across nearly all physiological systems. Examples of this include: 

• Neurological function: Brain development, cognitive performance, and vulnerability to neurodegenerative diseases differ between sexes.

• Immune response: Women generally exhibit stronger immune responses, influencing susceptibility to infections and autoimmune conditions.

• Pharmacokinetics and pharmacodynamics: sex can influence how drugs are absorbed, distributed, metabolised, and excreted, resulting in varied therapeutic outcomes and side-effect profiles. 

  
  

Failing to account for these differences can lead to incomplete or misleading data, ultimately compromising patient safety and the effectiveness of medical treatments.

Challenges and Misconceptions

Despite progress, barriers remain:

• Myths about variability: The belief that female animals introduce more variability due to hormonal cycles has been consistently disproven. In fact, male subjects often display equal or greater variability in physiological and behavioural measures. 

• Resource constraints: Including both sexes can increase sample sizes and associated costs - though the article argues that the long-term benefits to scientific accuracy and public health far outweigh these short-term burdens.

• Lack of training and awareness: Many researchers are still unaware of how to adequately design studies that include sex as a variable, or how to statistically analyse sex-specific effects.

Practical Steps for Researchers 

To bridge the gap between policy and practice, researchers can adopt the following hands-on approaches in their day-to-day lab work:

• Balance sex in study design: Proactively include equal numbers of male and female animals in experimental groups, and document their sex in all protocols and records.

• Track the oestrous cycle when relevant: For studies where hormonal status might influence outcomes, consider simple, non-invasive methods (e.g. vaginal cytology) to monitor the oestrous cycle in female rodents. This allows for more granular interpretation without excluding females.

• Report data by sex: Always report and analyse results separately for males and females, even if no significant sex difference is found — this transparency is essential for future meta-analyses.

• Use factorial designs: Implement statistical designs (e.g. two-way ANOVAs) that incorporate sex as a factor, rather than using it as a covariate or controlling for it, which can mask true differences.

• Pilot studies: Use small preliminary studies to identify sex-specific trends and inform power calculations for full-scale experiments.

• Educate members of the research group: Incorporate SABV training into lab onboarding and group meetings. Make it part of the lab culture, not just compliance.

• Collaborate with statisticians early: Engage with biostatisticians at the planning stage to ensure robust sex-based analyses and avoid underpowered subgroup comparisons.

  
  

By embedding these practices into routine workflows, researchers can go beyond policy compliance and meaningfully contribute to a more comprehensive and equitable understanding of biology.

Recommendations for the Future

To continue moving forward, the article offers several recommendations: 

1. Integrating SABV into training programmes for researchers at all levels.

2. Developing robust statistical guidelines to analyse sex differences appropriately.

3. Incentivising compliance through funding and journal publication requirements.

Promoting interdisciplinary collaboration to better understand complex sex-specific differences. 

Final Thoughts

"good science is inclusive science"

"Navigating the Paradigm Shift of Sex-Inclusive Preclinical Research" offers a compelling, data-driven narrative that challenges outdated norms and presents a vision for a more inclusive and scientifically rigorous future. It reminds us that ‘good’ science is inclusive science and that understanding sex differences is essential, not only for academic knowledge, but for developing effective treatment outcomes. 

📚 Read the full article here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12041288/

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This article was written by Neave Smith and edited by Rebecca Pope, with graphics produced by Suzana Sultan. If you enjoyed this article, be the first to be notified about new posts by signing up to become a WiNUK member (top right of this page)! Interested in writing for WiNUK yourself? Contact us through the blog page and the editors will be in touch.