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Background: Vaccines are one of the greatest achievements in public health. Prevalence and clinical significance of emerging postapproval, vaccine-related safety issues have not been systematically studied.Objective: To explore postmarketing safety modifications in U.S. Food and Drug Administration (FDA)-approved vaccine labels.Design: Retrospective cohort study.Setting: United States.Participants: Initial and subsequent labels of all vaccines that were FDA-approved between 1 January 1996 and 31 December 2015.Measurements: The primary aim was a descriptive analysis of the prevalence and characteristics of postapproval, safety-related label changes. The secondary aim was to describe the distribution of data sources triggering these modifications.Results: The study cohort comprised 57 FDA-approved vaccines. Initial approval for 53 (93%) of the vaccines was supported by randomized controlled trials, with a median cohort size of 4161 participants (interquartile range, 2204 to 8634 participants). There were 58 postapproval, safety-related label modifications associated with 25 vaccines (49 warnings and precautions, 8 contraindications, and 1 safety-related withdrawal). The initial approval trial characteristics were similar in vaccines with and without postmarketing, safety-related label modifications. The most common safety issue triggering label modifications was expansion of population restrictions (n = 21 [36%]), followed by allergies (n = 13 [22%]). The most common source of safety data was postmarketing surveillance (n = 28 of 58 [48%]).Limitation: The data source of the initial signal triggering safety-related label changes may not necessarily represent all safety data received and processed by the FDA.Conclusion: Over a 20-year period, vaccines were found to be remarkably safe. A large proportion of safety issues were identified through existing postmarketing surveillance programs and were of limited clinical significance. These findings confirm the robustness of the vaccine approval system and postmarketing surveillance.Primary Funding Source: None. [ABSTRACT FROM AUTHOR]

Background: Although regulatory changes towards correcting the underrepresentation of women in randomized controlled trials (RCTs) occurred (National Institutes of Health 1994), concerns exist about whether an improvement is taking place. In this systematic review and meta-analysis, we aimed to assess the inclusion rates of women in recent RCTs and to explore the potential barriers for the enrollment of women., Methods: RCTs published in 2017 examining any type of intervention in adults were searched in PubMed and Cochrane Library. The following predefined medical fields were included: cardiovascular diseases, neoplasms, endocrine system diseases, respiratory tract diseases, bacterial and fungal infections, viral diseases, digestive system diseases, and immune system diseases. Studies were screened independently by two reviewers, and an equal number of studies was randomly selected per calendric month. The primary outcome was the enrollment rate of women, calculated as the number of randomized women patients divided by the total number of randomized patients. Rates were weighted by their inverse variance; statistical significance was tested using general linear models (GLM)., Results: Out of 398 RCTs assessed for eligibility, 300 RCTs were included. The enrollment rate of women in all the examined fields was lower than 50%, except for immune system diseases [median enrollment rate of 68% (IQR 46 to 81)]. The overall median enrollment rate of women was 41% (IQR 27 to 54). The median enrollment rate of women decreased with older age of the trials' participants [mean age of trials' participants ≤ 45 years: 47% (IQR 30-64), 46-55 years: 46% (IQR 33-58), 56-62 years: 38% (IQR 27-50), ≥ 63 years: 33% (IQR 20-46), p < 0.001]. Methodological quality characteristics showed no significant association with the enrollment rates of women. Out of the 300 included RCTs, eleven did not report on the number of included women. There was no significant difference between these studies and the studies included in the analysis., Conclusions: Women are being inadequately represented, in the selected medical fields analyzed in our study, in recent RCTs. Older age is a potential barrier for the enrollment of women in clinical trials. Low inclusion rates of elderly women might create a lack of crucial knowledge in the adverse effects and the benefit/risk profile of any given treatment. Factors that might hinder the participation of women should be sought and addressed in the design of the study., (© 2022. The Author(s).)

Background: Infections caused by multidrug-resistant (MDR) bacteria are a major public health threat. We aimed to assess the data supporting US Food and Drug Administration (FDA) approval of new agents aimed to treat MDR bacterial infections and the data provided by postmarketing studies., Methods: We identified all drugs with in vitro activity against MDR bacteria initially approved by the FDA between January 2010 and December 2018. Characteristics of trials supporting approval and regulatory pathways were collected from Drugs@FDA. Characteristics of postmarketing studies were extracted from drug labels and ClinicalTrials.gov entries effective 1 June 2019., Results: Initial approval of 11 newly approved antibiotics with anti-MDR activity was supported by 20 trials, all with noninferiority design. All initially approved indications were for common infections, mostly acute bacterial skin and skin-structure infections, regardless of causative microorganism. The proportion of MDR bacteria in most trials was low (<10% for gram-negative infections, <1% for gram-positive pneumonia). Most trials (90%) excluded immunocompromised and critically ill patients. Of 16 additional postmarketing randomized controlled trials identified through ClinicalTrials.gov, only 2 exclusively included infections caused by MDR bacteria, comprising 116 patients. No drug was granted accelerated approval, which would mandate postmarketing efficacy studies., Conclusions: The approval of new drugs with potential clinical activity against MDR bacteria is supported by trials evaluating infections caused by non-MDR organisms, using noninferiority design and excluding the patients most likely to require these agents. Subsequent postmarketing efficacy data against these organisms are scarce. Healthcare professionals and regulators should demand more robust data to support clinical decision making., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Vaccines have changed modern medicine, and are a mainstay in reducing morbidity and mortality from infections. Our research group recently published a study in which we found that vaccines approved by the US Food and Drugs Administration were safe with few clinically important post-approval adverse effects. The current COVID-19 pandemic presents regulators with the unprecedented challenge of balancing a public demand for the rapid development and approval of a safe and effective SARS-CoV-2 vaccine without compromising the strict pre-marketing requirements used for previous vaccines. Here, we review the approval process and safety profiles of FDA approved vaccines and discuss some of the challenges currently facing the FDA regarding the SARS-CoV-2 vaccine approval.

Background: There is no consensus on the optimal management of immunosuppression during bacterial infections among solid organ transplant recipients., Methods: A multicenter, cross-sectional survey, of high-volume kidney and liver transplant centers across US and Europe. Structured questionnaires including six multiple-choice questions concerning the management of immunosuppression during infection were distributed among 381 centers., Results: A total of 124 (33%) centers fully completed the questionnaire: 67 liver, 57 kidney centers. Participating centers reported heterogenous approaches to immunosuppression management for all types of immunosuppressive drugs. Notably, kidney centers reported similar frequencies of either discontinuation (19%), continuation (19%), or dose reduction (17.5%) of antimetabolites; discontinuation only for life-threatening infection (17.5%) or case by case decisions (27%). Calcineurin inhibitors (CNI) management was heterogenous mostly among liver centers, with 8% discontinuing the CNI, 18% continuing, and 22% reducing dose. Heterogenous approaches to management of steroids and inhibitors of the mammalian target of rapamycin were also demonstrated., Conclusions: Immunosuppression management during bacterial infection is heterogenous in US and European centers. Immunosupression reduction (ISR) during infection is a common practice, though supported by limited evidence. Demonstrating high heterogeneity in the approach to ISR, together with the equivocal results of clinical studies, support consideration of an interventional clinical trial., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)