Considering Sex and Gender in Therapeutics throughout the Product Life Cycle: A Narrative Review and Case Study of Gilteritinib.

Background: Biological sex-related factors influence pharmacokinetic, pharmacodynamic, and disease processes that may affect the predictability of drug dosing and adverse effects, which may in turn have clinical consequences for patients' lives. Nonetheless, sex-related factors are not always taken into account in clinical trial design or clinical decision-making, for multiple reasons, including a paucity of studies that clearly and objectively study and measure sex-disaggregated and sex-related outcomes, as well as gaps in regulatory and policy structures for integrating these considerations. Objectives: To complete a narrative review and use a case study to understand available evidence, inform future research, and provide policy considerations that incorporate information on sex- and gender-related factors into clinician-facing resources. Methods: A comprehensive review of available literature was conducted using a sex- and gender-based analysis plus (SGBA Plus) approach to identify sex- and/or gender-disaggregated information for gilteritinib, a chemotherapeutic agent. Systematic searches were performed in MEDLINE (Ovid), Embase (Ovid), CENTRAL (Wiley), International Pharmaceutical Abstracts (Ovid), Scopus, and ClinicalTrials.gov, from inception to March 18, 2021. The information was then summarized and compared with the Canadian product monograph for this drug. Results: Of 311 records screened, 3 provided SGBA Plus information as a component of outcomes, rather than just as categories or demographic characteristics. Of these, 2 were case studies, and 1 was a clinical trial. No studies from the ClinicalTrials.gov database that were in progress at the time of this review provided details about sex-disaggregated outcomes. The Canadian product monograph did not include sex-disaggregated outcome data. Conclusions: The available evidence from clinical trials, other published literature, and guidance documents does not provide details about sex-disaggregated outcomes for gilteritinib. This paucity of available evidence may create a challenge for clinicians who are making decisions about the efficacy and safety of prescribed therapies in sex-specific populations that have not been well studied.

Contexte: Les facteurs liés au sexe biologique influencent les processus pharmacocinétiques, pharmacodynamiques et pathologiques, qui peuvent avoir une incidence sur la prévisibilité du dosage des médicaments et des effets indésirables. Ceci peut à son tour avoir des conséquences cliniques sur la vie des patients. Néanmoins, les facteurs liés au sexe ne sont pas toujours pris en compte dans la conception des essais cliniques ou la prise de décision clinique, et cela pour de nombreuses raisons ­ notamment le manque d'études qui examinent et mesurent clairement et objectivement les résultats ventilés par sexe et liés au sexe ainsi que les lacunes dans les réglementations et structures politiques pour intégrer ces considérations. Objectifs: Mener un examen narratif et utiliser une étude de cas pour comprendre les preuves disponibles, éclairer les recherches futures et fournir des considérations politiques qui intègrent des informations sur les facteurs liés au sexe et au genre dans les ressources destinées aux cliniciens. Méthodes: Une revue complète de la littérature disponible a été réalisée à l'aide d'une analyse comparative fondée sur le sexe et le genre Plus (ACSG Plus) pour identifier les informations ventilées par sexe et/ou par genre pour le giltéritinib, un agent chimiothérapeutique. Des recherches systématiques ont été effectuées dans MEDLINE (Ovid), Embase (Ovid), CENTRAL (Wiley), International Pharmaceutical Abstracts (Ovid), Scopus et ClinicalTrials.gov, depuis la création de chaque base de données jusqu'au 18 mars 2021. Ces informations ont ensuite été résumées et comparées avec la monographie canadienne de produit pharmaceutique pour ce médicament. Résultats: Sur les 311 documents examinés, 3 ont fourni des informations ACSG Plus en tant que composante des résultats, plutôt que simplement en tant que catégories ou caractéristiques démographiques. Parmi ceux-ci, 2 étaient des études de cas et 1 était un essai clinique. Aucune étude de la base de données ClinicalTrials.gov en cours au moment de cette revue n'a fourni de détails sur les résultats ventilés par sexe. La monographie de produit canadienne ne comprenait pas de données sur les résultats ventilées par sexe. Conclusions: Les preuves disponibles issues d'essais cliniques, d'autres publications et de documents d'orientation ne fournissent pas de détails sur les résultats ventilés par sexe pour le giltéritinib. Ce manque d'éléments probants disponibles peut constituer un défi pour les cliniciens qui prennent des décisions sur l'efficacité et l'innocuité des thérapies prescrites chez des populations sexospécifiques qui n'ont pas été bien étudiées.

Guidelines for Diagnosis and Management of Infective Endocarditis in Adults: A WikiGuidelines Group Consensus Statement.

Importance: Practice guidelines often provide recommendations in which the strength of the recommendation is dissociated from the quality of the evidence. Objective: To create a clinical guideline for the diagnosis and management of adult bacterial infective endocarditis (IE) that addresses the gap between the evidence and recommendation strength. Evidence Review: This consensus statement and systematic review applied an approach previously established by the WikiGuidelines Group to construct collaborative clinical guidelines. In April 2022 a call to new and existing members was released electronically (social media and email) for the next WikiGuidelines topic, and subsequently, topics and questions related to the diagnosis and management of adult bacterial IE were crowdsourced and prioritized by vote. For each topic, PubMed literature searches were conducted including all years and languages. Evidence was reported according to the WikiGuidelines charter: clear recommendations were established only when reproducible, prospective, controlled studies provided hypothesis-confirming evidence. In the absence of such data, clinical reviews were crafted discussing the risks and benefits of different approaches. Findings: A total of 51 members from 10 countries reviewed 587 articles and submitted information relevant to 4 sections: establishing the diagnosis of IE (9 questions); multidisciplinary IE teams (1 question); prophylaxis (2 questions); and treatment (5 questions). Of 17 unique questions, a clear recommendation could only be provided for 1 question: 3 randomized clinical trials have established that oral transitional therapy is at least as effective as intravenous (IV)-only therapy for the treatment of IE. Clinical reviews were generated for the remaining questions. Conclusions and Relevance: In this consensus statement that applied the WikiGuideline method for clinical guideline development, oral transitional therapy was at least as effective as IV-only therapy for the treatment of IE. Several randomized clinical trials are underway to inform other areas of practice, and further research is needed.

Sex, Gender, and the Regulation of Prescription Drugs: Omissions and Opportunities.

The regulation of prescription drugs is an important health, safety, and equity issue. However, regulatory processes do not always consider evidence on sex, gender, and factors such as age and race, omissions that advocates have highlighted for several decades. Assessing the impact of sex-related factors is critical to ensuring drug safety and efficacy for females and males, and for informing clinical product monographs and consumer information. Gender-related factors affect prescribing, access to drugs, needs and desires for specific prescribed therapies. This article draws on a policy-research partnership project that examined the lifecycle management of prescription drugs in Canada using a sex and gender-based analysis plus (SGBA+) lens. In the same time period, Health Canada created a Scientific Advisory Committee on Health Products for Women, in part to examine drug regulation. We report on grey literature and selected regulatory documents to illustrate the extent to which sex and gender-based analysis plus (SGBA+) is utilized in regulation and policy. We identify omissions in the management of prescription drugs, and name opportunities for improvements by integrating SGBA+ into drug sponsor applications, clinical trials development, and pharmacovigilance. We report on recent efforts to incorporate sex disaggregated data and recommend ways that the management of prescription drugs can benefit from more integration of sex, gender, and equity.

Antimicrobial susceptibility testing: An updated primer for clinicians in the era of antimicrobial resistance: Insights from the Society of Infectious Diseases Pharmacists.

Antimicrobial susceptibility testing (AST) is a critical function of the clinical microbiology laboratory and is essential for optimizing care of patients with infectious diseases, monitoring antimicrobial resistance (AMR) trends, and informing public health initiatives. Several methods are available for performing AST including broth microdilution, agar dilution, and disk diffusion. Technological advances such as the development of commercial automated susceptibility testing platforms and the advent of rapid diagnostic tests have improved the rapidity, robustness, and clinical application of AST. Numerous accrediting and regulatory agencies are involved in the process of AST and setting and revising breakpoints, including the U.S. Food and Drug Administration and the Clinical and Laboratory Standards Institute. Challenges to optimizing AST include the emergence of new resistance mechanisms, the development of new antimicrobial agents, and generation of new data requiring updates and revisions to established methods and breakpoints. Together, the challenges in AST methods and their interpretation create important opportunities for well-informed clinicians to improve patient outcomes and provide value to antimicrobial stewardship programs, especially in the setting of rapidly changing and increasing AMR. Addressing AST challenges will involve continued development of new technologies along with collaboration between clinicians and the laboratory to facilitate optimal antimicrobial use, combat the increasing burden of AMR, and inform the development of novel antimicrobials. This updated primer serves to reinforce important principles of AST, and to provide guidance on their implementation and optimization.

A Sex- and Gender-Based Analysis of Adverse Drug Reactions: A Scoping Review of Pharmacovigilance Databases.

Drug-related adverse events or adverse drug reactions (ADRs) are currently partially or substantially under-reported. ADR reporting systems need to expand their focus to include sex- and gender-related factors in order to understand, prevent, or reduce the occurrence of ADRs in all people, particularly women. This scoping review describes adverse drug reactions reported to international pharmacovigilance databases. It identifies the drug classes most commonly associated with ADRs and synthesizes the evidence on ADRs utilizing a sex- and gender-based analysis plus (SGBA+) to assess the differential outcomes reported in the individual studies. We developed a systematic search strategy and applied it to six electronic databases, ultimately including 35 papers. Overall, the evidence shows that women are involved in more ADR reports than men across different countries, although in some cases, men experience more serious ADRs. Most studies were conducted in higher-income countries; the terms adverse drug reactions and adverse drug events are used interchangeably, and there is a lack of standardization between systems. Additional research is needed to identify the relationships between sex- and gender-related factors in the occurrence and reporting of ADRs to adequately detect and prevent ADRs, as well as to tailor and prepare effective reporting for the lifecycle management of drugs.

A randomized controlled trial to assess the influence of a picture-based antiemetic medication calendar on medication-taking behavior in adults receiving chemotherapy.

OBJECTIVE: A prospective open-label randomized controlled trial to assess the role of a picture-based medication calendar on adherence to antiemetic regimens for adult patients receiving chemotherapy and assess the effect on other medication taking behaviors as well as patient satisfaction with the tool. METHODS: Participants were randomly assigned 1:1 to routine care with or without calendar. RESULTS: Adherence, stratified by education (university or postgraduate, p = 0.09; grade school, high school or college p = 0.32), was non-significantly different between study arms. At least 70% of intervention arm participants moderately or completely agreed that the calendar helped with medication taking behaviors. There was no statistical difference between study arms for perceived regimen complexity (p = 0.16). Medication Use and Self Efficacy score (adjusted for age) used to assess perceived self-efficacy with medication taking behaviors were not statistically significant between study arms (p = 0.09). CONCLUSION: The picture-based medication calendar did not statistically affect adherence to scheduled antiemetics among outpatients receiving chemotherapy for solid organ tumor origins. However, participants indicated that the calendar was effective for keeping track of medications, had an easy-to-understand layout, and provided help around when and how to take medications related to the oncology regimen.

Risk of falls associated with antiepileptic drug use in ambulatory elderly populations: A systematic review.

BACKGROUND: Falls are a major cause of morbidity and mortality in older adults. About a third of those aged 65 years or older fall at least once each year, which can result in hospitalizations, hip fractures and nursing home admissions that incur high costs to individuals, families and society. The objective of this clinical review was to assess the risk of falls in ambulatory older adults who take antiepileptic drugs, medications that can increase fall risk and decrease bone density. METHODS: PubMed, EMBASE, MEDLINE and the Cochrane Library electronic databases were searched from inception to July 2014. Case-control, quasi-experimental and observational design studies published in English that assessed quantifiable fall risk associated with antiepileptic drug use in ambulatory patient populations with a mean or median age of 65 years or older were eligible for inclusion. One author screened all titles and abstracts from the initial search. Two authors independently reviewed and abstracted data from full-text articles that met eligibility criteria. RESULTS: Searches yielded 399 unique articles, of which 7 met inclusion criteria-4 prospective or longitudinal cohort studies, 1 cohort study with a nested case-control, 1 cross-sectional survey and 1 retrospective cross-sectional database analysis. Studies that calculated the relative risk of falls associated with antiepileptic drug use reported a range of 1.29 to 1.62. Studies that reported odds ratios of falls associated with antiepileptic drug use ranged from 1.75 to 6.2 for 1 fall or at least 1 fall and from 2.56 to 7.1 for more frequent falls. DISCUSSION: Health care professionals should monitor older adults while they take antiepileptic drugs to balance the need for such pharmacotherapy against an increased risk of falling and injuries from falls.