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Clinical trials, says neuroscientist Antonella Santuccione Chadha,MD, usually have one thing in common: Their results are not stratified on the basis of sex. That lack of sex- and gender-based analysis, says Santuccione Chadha, chief medical officer, Altoida, and pro bono CEO of the Women’s Brain Project, negatively impacts the whole of society. Santuccione Chadha spoke with Applied Clinical Trials.
Applied Clinical Trials: What is the Women’s Brain Project advocating for?
Antonella Santuccione Chadha: WBP is urging that sex and gender analysis consistently and routinely occur from the preclinical stage; at the inception of drug development characterization; and onward throughout the drug’s testing. WBP is not advocating for proof of intellectual superiority or any type of superiority of one sex over another. We need to understand if sex-based efficacy and safety differences exist in any drug compound under consideration. Once the therapy is approved, then we need to see how sex-based differences affect healthcare costs and patient outcomes.
ACT: Would you cite a few examples of therapeutic-related, significant differences between men and women?
ASC: Zolpidem, for which regulatory agencies had to revise the label to halve the medication for women because the original dose was too strong? It has been long known that women experience more adverse effects than men from vaccines—and this was before the pandemic.1 But results from the COVID-19 trials were rarely analyzed for sex and gender safety differences.2 Women develop Alzheimer’s at a higher rate than men do, but in a review of 56 randomized trials of Alzheimer therapies, just 7 reported sex-differentiated outcomes.3 As for the approved immunotherapy medications for Alzheimer’s, data that the WBP reviewed of the first two showed that men responded better to the medication than women. We do know that the trials of the newly approved medication, lecanemab, has shown noteworthy sex differences, precisely, the cognitive benefit of the drug was evident primarily in men.4
Those results will be discussed at an upcoming conference. The WBP is planning to analyze the pooled data to see if the differences are statistically significant, and if this trend continues in post analysis.
ACT: A short review of PubMed shows that some researchers are differentiating findings between sex and gender and advocating that others do as well.
ASC: But are they starting in the preclinical setting? It has long been recognized that it needs to. When the ICH (International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use) issued its first guidance, ICH said in its directive for toxicity determination that both genders of experimental animals “should generally be used or justification given for specific omissions.”5 (FDA has adopted the same guidance).6
ACT: Why hasn’t that directive been universally followed?
ASC: For various reasons. Some researchers have felt that including sex as a variable in all studies would be a waste of resources, or it would lengthen the time of the study because of the extra work involved, or it would unduly increase the number of animals used in the research. Fields et al wrote in 2014 that the NIH “should be promoting research into the sex differences that are important to science and in disease.”7 But how do you determine what is important unless you investigate?
ACT: So why the urgency now?
ASC: Again, a few reasons. For one, defining sex and gender differences is the gateway to precision medicine. There is ethnicity, there is race, there is geography; individuals have a specific impact on clinical outcomes. Including the regular analysis of sex and gender differences is just an entry point. There are huge amounts of other data that can be captured, categorized, analyzed, and then understood. The data are there, it just takes time and some money to analyze them.
ACT: Which is why you say that excluding sex and gender analysis impacts all of society.
ACT: And the other reason?
ASC: The advancement of technology. Digital biomarkers, big data, artificial intelligence—these are tools that we now must use to make sense of the findings. Digital biomarkers are vital to neurology investigation, they can provide incredible amounts of information. The AI-driven Altoida platform, which assesses whether a person has or is developing cognitive deficiencies, can tell if the user is a man or a woman. AI is a great tool to show biases in the data. The more diverse data that are fed into an AI system, the larger the screening capacity will be.
ACT: And industry’s reaction?
ASC: Pharma recognizes the value that digital biomarkers can play in pinpointing effective therapies. The Altoida digital platform is now embedded in a few Phase II trials and one Phase III trial and in a Phase IV registry which we are conducting together with Eisai in Greece. When we started the WBP in 2017, the attitude in the field was, ‘do we really need it?’ Then we started publishing, including a paper last June detailing the need to use digital biomarkers in neurological assessment and capturing sex and gender difference in the early phase of AD.8 We also have shown the economic impact of not including sex and gender-based analysis in a therapy’s development.8 And last November, we spoke at the 15th Clinical Trials on Alzheimer’s Disease conference.9