Sex-Divergent Clinical Outcomes and Precision Medicine: An Important New Role for Institutional Review Boards and Research Ethics Committees

Abstract

The efforts toward individualized medicine have constantly increased in an attempt to improve treatment options. These efforts have led to the development of small molecules which target specific molecular pathways involved in cancer progression. We have reviewed preclinical studies of sunitinib that incorporate sex as a covariate to explore possible sex-based differences in pharmacokinetics and drug–drug interactions (DDI) to attempt a relationship with published clinical outputs. We observed that covariate sex is lacking in most clinical outcome reports and suggest a series of ethic-based proposals to improve research activities and identify relevant different sex outcomes. We propose a deeper integration of preclinical, clinical, and translational research addressing statistical and clinical significance jointly; to embed specific sex-divergent endpoints to evaluate possible gender differences objectively during all stages of research; to pay greater attention to sex-divergent outcomes in polypharmacy scenarios, DDI and bioequivalence studies; the clear reporting of preclinical and clinical findings regarding sex-divergent outcomes; as well as to encourage the active role of scientists and the pharmaceutical industry to foster a new scientific culture through their research programs, practice, and participation in editorial boards and Institutional Ethics Review Boards (IRBs) and Research Ethics Committees (RECs). We establish the IRB/REC as the centerpiece for the implementation of these proposals. We suggest the expansion of its competence to follow up clinical trials to ensure that sex differences are addressed and recognized; to engage in data monitoring committees to improve clinical research cooperation and ethically address those potential clinical outcome differences between male and female patients to analyze their social and clinical implications in research and healthcare policies.

Trends in sex-specific differences in outcomes in extreme preterms: progress or natural barriers?

“…Furthermore, a subanalysis in a randomised trial of prophylactic indomethacin showed that the intervention reduced the rate of severe IVH in boys more than in girls 43. Future studies should similarly perform sex-differentiated data analysis to identify differential treatment effects between boys and girls 28. If sex is found to modulate the clinical outcomes of a treatment, then patient management may hypothetically be adjusted individually and tenets of precision medicine can be realised.…”

“…Evaluation of longitudinal trends in sex-specific care practices, mortality and major morbidities among preterm neonates is important for counselling families, optimising existing interventions and personalising interventions in a sex-specific manner to improve outcomes, which is a concept highlighted as precision medicine 28. Our objective was to investigate the differences in outcomes of preterm boys and girls born at <29 weeks’ gestation and evaluate the trend of rate differences to identify any change over 10 years.…”

Improving transparency and scientific rigor in academic publishing

“…This policy is not a mandate to specifically investigate sex differences, but requires investigators to consider sex from the design of the research question through reporting the results (Clayton, ). In some instances, sex might not influence the outcomes (e.g., Fritz, Amrein, & Wolfer, ; Segarra, Modamio, Fernandez, & Marino, ), but balancing sex in animal and cellular models will distinctly inform the various levels of research (Clayton, ). More specific guidelines for applying the policy of considering sex as a biological variable are also available (Clayton, ; McCarthy, Woolley, & Arnold, ), but shifting the experimental group composition should be done in the context of appropriate a priori power analyses.…”

Diversity and inclusion for the All of Us research program: A scoping review

“…Several of the articles call for more comparison of research findings by sex, noting that, like race and ethnicity, sex differences in many domains are still widely understudied. [56][57][58][59][60] Regardless of actual representation of females in biomedical research, many health outcomes specific to them will remain unknown unless researchers prioritize exploring differences across sex assigned at birth, race, and ethnicity. In addition, sex is predominantly perceived as a binary biological construct and individuals born as intersex, or those with disorders of sexual development, have difficulties "fitting" into a male/female binary category.…”