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.
Highlights
The research drive toward personalized medicine has grown exponentially during the last years in an attempt to improve therapeutic outcomes putting the patient at the center of the healthcare system
The pharmacokinetic differences between male and female sexes may be responsible for the large variability and lack of efficacy encountered in some clinical trials which led to the change or discontinuation of treatment (Lankheet et al, 2014b; Akaza et al, 2015; Gore et al, 2015; Barrios et al, 2016; Domagała-Haduch et al, 2016) likely due to poor dosing adjustment since plasma concentration alone may not ensure precise dose adjustment (Houk et al, 2010; Lankheet et al, 2014b) as seen in most tyrosine kinase (TK) inhibitors
The Institutional Review Board (IRB) and Research Ethics Committee (REC), together with the pharmaceutical industry and other research sponsors play a key role to ensure that possible differences between male and female patients are identified, taken into account and an assessment of their clinical relevance performed
Summary
The research drive toward personalized medicine has grown exponentially during the last years in an attempt to improve therapeutic outcomes putting the patient at the center of the healthcare system. Further cumulative evidence has matured in various fields (Klein et al, 2015) including neurosciences (Cahill, 2006, 2017), neurodegenerative diseases (Bove and Chitnis, 2013; Canevelli et al, 2017), medication use and treatment adherence (Chen et al, 2014; Manteuffel et al, 2014), incidence of DDI (Bowlin et al, 2013) as well as clinical and preclinical research (Franconi and Campesi, 2014a,b; Mazure, 2016; Segarra et al, 2016) This evidence has pushed forward more clearly the need to address potential sex-based differential clinical effects on male and female patients with the inclusion of covariate sex in the outcome analysis for the benefit of patients (Segarra et al, 2016; Cahill, 2017)
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