Sex Differences and Implications for Translational Neuroscience Research Workshop Summary (2011) / Chapter Skim
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5 Sex Differences in Drug Development: Policy and Practice
5 Sex Differences in Drug Development: Policy and Practice
Pages 59-72
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From page 59... ...
, the National Institutes of Health, and industry discussed the history, guidelines, and regulations regarding the inclusion of males and females in clinical trials, and how and when industry considers and addresses the study of sex differences, given current regulatory requirements. SEx DIFFERENCES IN TRANSLATIONAL NEuROSCIENCE: A vIEW FROM INDuSTRy Those in the neuroscience field would generally agree that there are significant sex-based differences in how the brain works, and in diseases of the nervous system, Sheng said.
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Considering Sex Differences in Drug Development Sex differences can provide information about disease mechanisms and clues about why people contract a disease. Sex differences also affect the quality of animal disease models, and should guide choices of animal models.
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. Experimental studies are also possible if the basic pathogenesis of that disease is understood, and if there is a reasonable animal model in which to study the potential sex difference.
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Given the lack of good animal models, the difficulty in accounting for sex differences, and the fact that not enough is known about the basic mechanism of Alzheimer's disease, drug discovery is more likely to be successful by focusing on some of these other factors. Another neurodegenerative disease being studied is amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease)
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As a result, studying relevant neuropsychiatric sex differences is difficult in preclinical experiments. Another primary hurdle in studying sex differences in these diseases is the lack of good animal models.
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Therefore, for many indications, studying sex differences may not be completely appropriate yet. In some cases, the most valuable investment of resources may be in basic neuroscience, to gain improved basic knowledge (and hence improved animal models)
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In 1993, following the GAO report, a new guideline was issued that reversed the 1977 policy of exclusion of women of childbearing potential from early trials. The guideline, Study and Ealuation of Gender Differences in the Clinical Ealuation of Drugs, recommended collection and analysis of data on sex differences for effectiveness, adverse events, and pharmacokinetics.
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In 2001, nearly 10 years after the 1992 GAO report, Congress requested that GAO again report on the status of women in clinical trials. This time GAO found that appropriate numbers of women were included in studies submitted as part of NDAs, and that participation of women was similar to that of men, except for the earliest phase clinical trials and in select therapeutic areas, particularly cardiovascular disease (GAO, 2001)
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To date little is known about the impact of sex difference in response to depression treatment. Neurobiological parameters may be valuable in predicting treatment response, and may better explain variance in response than common subdiagnostic
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This is a step toward personalized health care. PRACTICAL ISSuES OF ADDRESSING SEx DIFFERENCES DuRING TRANSLATIONAL RESEARCH AND CLINICAL DRuG DEvELOPMENT Douglas Feltner, vice president of Global Translational Medicine and Neuroscience at Pfizer Inc, reviewed some of the practical issues in drug development.
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Key data are necessary before exposing women of childbearing potential to an investigational product, including one that has potential maternal and fetal toxicity, which is derived from embryo-fetal development studies in rats and rabbits. Female and male fertility studies are completed prior to initiation of Phase III trials, and pre- and postnatal development studies are completed prior to submission of the NDA.
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Stevin Zorn, workshop cochair, noted that many animal models used in drug discovery research were developed more than 50 years ago, when clinicians and basic animal researchers worked closely together to model human diseases. Given what is now known about the complexities of diseases, and the impacts of not just single, but multiple, genetic defects, it is time to get basic and clinical researchers back together to reevaluate what the animal models are, what information the models can provide, and what can be modeled.
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Statistics show that an individual with two comorbid anxiety disorders has a 50 percent chance of having a third. With three or four comorbid anxiety disorder diagnoses, why not just have an anxiety disorder across all of the comorbidities and focus on that?
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