Comparative Benefits and Risks Associated with Currently Authorized COVID-19 Vaccines.

This article provides a systematic assessment of the efficacy, risks, and methodological quality of evidence from five major publicly available vaccine trials. Results from Pfizer-BioNTech mRNA, Moderna-US NIH mRN-1273, AstraZeneca-Oxford ChAdOx1 nCov-19, Gamaleya GamCovidVac (Sputnik V), and Ad26.COV2.S Johnson & Johnson vaccines were included. Extracted benefits and risks data from each trial were summarized using the GRADE approach denoting the overall certainty of evidence along with relative and absolute effects. Relative risk reduction across all five vaccine trials ranged from 45% to 96%. Absolute risk reduction in symptomatic COVID-19 ranged from 6 to 17 per 1000 across trials. None of the vaccines were associated with a significant increase in serious adverse events compared to placebo. The overall certainty of evidence varied from low to moderate. All five vaccines are effective and safe, but suggest room for improvement in the conduct of large-scale vaccine trials. Certainty of evidence was downrated due to risk of bias, which can be mitigated by improving transparency and thoroughness in conduct and reporting of outcomes.

Family Needs After Traumatic Brain Injury: A VA TBI Model Systems Study.

OBJECTIVE: To describe the self-reported needs of family caregivers of service members and veterans (SMVs) who sustained a traumatic brain injury (TBI) and to identify predictors of the unmet family caregiver needs. SETTING: Five Department of Veterans Affairs (VA) Polytrauma Rehabilitation Centers (PRCs). PARTICIPANTS: Family caregivers of SMVs enrolled in the VA PRC TBI Model Systems (TBIMS) national database who were within their first 5 years post-TBI ( n = 427). DESIGN: Observational study. MAIN OUTCOME MEASURE: The Family Needs Questionnaire-Revised (FNQ-R) was completed by each SMV's designated caregiver. ANALYSES: Descriptive analyses were conducted on the FNQ-R responses at the item, domain, and total score levels. Unadjusted univariable and adjusted multivariable regression models were fitted to identify predictors of total unmet needs and unmet family need domains. RESULTS: FNQ-R item-level and domain-level descriptive results indicated that health information was the most frequently met need domain. In contrast, emotional and instrumental support domains were the least often met. On average, family caregivers reported that 59.2% of the 37 FNQ-R needs were met at the time of the follow-up assessment. Regression models indicated that both the number of SMV-perceived environmental barriers and whether the SMV received mental health treatment within the past year predicted the number of unmet FNQ-R needs. SMV-reported environmental barriers predicted increased unmet needs in all 6 family caregiver domains, and SMV mental health treatment in the past year predicted more unmet family caregiver emotional support, community support, and professional support needs. CONCLUSIONS: The current findings can be used to inform policy and programming for VA and Department of Defense to proactively address the specific needs of families and caregivers experienced in the first 5 years post-TBI.

Perception of Medical Student Mistreatment: Does Specialty Matter?

PURPOSE: Medical student mistreatment is pervasive, yet whether all physicians have a shared understanding of the problem is unclear. The authors presented professionally designed trigger videos to physicians from 6 different specialties to determine if they perceive mistreatment and its severity similarly. METHOD: From October 2016 to August 2018, resident and attending physicians from 10 U.S. medical schools viewed 5 trigger videos showing behaviors that could be perceived as mistreatment. They completed a survey exploring their perceptions. The authors compared perceptions of mistreatment across specialties and, for each scenario, evaluated the relationship between specialty and perception of mistreatment. RESULTS: Six-hundred fifty resident and attending physicians participated. There were statistically significant differences in perception of mistreatment across specialties for 3 of the 5 scenarios: aggressive questioning (range, 74.1%-91.2%), negative feedback (range, 25.4%-63.7%), and assignment of inappropriate tasks (range, 5.5%-25.5%) (P ≤ .001, for all). After adjusting for gender, race, professional role, and prior mistreatment, physicians in surgery viewed 3 scenarios (aggressive questioning, negative feedback, and inappropriate tasks) as less likely to represent mistreatment compared with internal medicine physicians. Physicians from obstetrics-gynecology and "other" specialties perceived less mistreatment in 2 scenarios (aggressive questioning and negative feedback), while family physicians perceived more mistreatment in 1 scenario (negative feedback) compared with internal medicine physicians. The mean severity of perceived mistreatment on a 1 to 7 scale (7 most serious) also varied statistically significantly across the specialties for 3 scenarios: aggressive questioning (range, 4.4-5.4; P < .001), ethnic insensitivity (range, 5.1-6.1; P = .001), and sexual harassment (range, 5.5-6.3; P = .004). CONCLUSIONS: Specialty was associated with differences in the perception of mistreatment and rating of its severity. Further investigation is needed to understand why these perceptions of mistreatment vary among specialties and how to address these differences.

US Food and Drug Administration Approvals of Drugs and Devices Based on Nonrandomized Clinical Trials: A Systematic Review and Meta-analysis.

Importance: The size of estimated treatment effects on the basis of which the US Food and Drug Administration (FDA) has approved drugs and devices with data from nonrandomized clinical trials (non-RCTs) remains unknown. Objectives: To determine how often the FDA has authorized novel interventions based on non-RCTs and to assess whether there is an association of the magnitude of treatment effects with FDA requirements for additional testing in randomized clinical trials (RCTs). Data Sources: Overall, 606 drug applications for the Breakthrough Therapy designation from its inception in January 2012 were downloaded from the FDA website in January 2017 and August 2018, and 71 medical device applications for the Humanitarian Device Exemption from its inception in June 1996 were downloaded in August 2017. Study Selection: Approved applications based on non-RCTs were included; RCTs, studies with insufficient information, duplicates, and safety data were excluded. Data Extraction and Synthesis: Data were extracted by 2 independent investigators. A statistical association of the magnitude of estimated effect (expressed as an odds ratio) with FDA requests for RCTs was assessed. The data were also meta-analyzed to evaluate the differences in odds ratios between applications that required further testing and those that did not. The results are reported according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Main Outcomes and Measures: Disease, laboratory, and patient-related outcomes, including disease response or patient survival, were considered. Results: Among 677 drug and medical device applications, 68 (10.0%) were approved by the FDA based on non-RCTs. Estimates of effects were larger when no further RCTs were required (mean natural logarithm of the odds ratios, 2.18 vs 1.12; odds ratios, 8.85 vs 3.06; P = .03). The meta-analysis results confirmed these findings: estimated effects were approximately 2.5-fold higher for treatments or devices that were approved based on non-RCTs than for treatments or devices for which further testing in RCTs was required (6.30 [95% CI, 4.38-9.06] vs 2.46 [95% CI, 1.70-3.56]; P < .001). Overall, 9 of 677 total applications (1.3%) that were approved on the basis of non-RCTs had relative risks of 10 or greater and 12 (1.7%) had relative risks of 5 or greater. No clear threshold above which the FDA approved interventions based on the magnitude of estimated effect alone was detected. Conclusions and Relevance: In this study, estimated magnitudes of effect were larger among studies for which the FDA did not require RCTs compared with studies for which it did. There was no clear threshold of treatment effect above which no RCTs were requested.

Medical Student Mistreatment-an Obstetrics and Gynecology Perspective: a Pilot Study.

OBJECTIVE: To determine if perception of mistreatment and severity in each of the professional videotaped vignettes was similar between participants of differing professional status (Ob/Gyn attending physicians, resident physicians, and medical students), previous mistreatment status, ethnic minority status, and gender. METHODS: Three video vignettes were filmed portraying possible medical student mistreatment during an obstetrics and gynecology clerkship. Prior to watching the videos, all participants were asked to complete a questionnaire related to their prior experience with mistreatment as a medical student along with other demographic details. After viewing each video, participants were asked to rate the video as representing mistreatment (yes/no) and, if yes, the severity of medical student mistreatment. RESULTS: Eight attending physicians, ten resident physicians, and ten medical students participated in this study. Professional status, previous mistreatment status, ethnic minority status, and gender did not affect how participants perceived mistreatment or the severity of the video vignettes. Fifty percent (14/28) of participants reported previous mistreatment as a medical student, all of which occurred during their third year of medical school. CONCLUSION: Medical students, resident physicians, and attending physicians generally agreed which video vignettes represented medical student mistreatment and the level of severity of the event.

Larger effect sizes in nonrandomized studies are associated with higher rates of EMA licensing approval.

OBJECTIVES: The aim of this study was to evaluate how often the European Medicines Agency (EMA) has authorized drugs based on nonrandomized studies and whether there is an association between treatment effects and EMA preference for further testing in randomized clinical trials (RCTs). STUDY DESIGN AND SETTING: We reviewed all initial marketing authorizations in the EMA database on human medicines between 1995 and 2015 and included authorizations granted without randomized data. We extracted data on treatment effects and EMA preference for further testing in RCTs. RESULTS: Of 723 drugs, 51 were authorized based on nonrandomized data. These 51 drugs were licensed for 71 indications. In the 51 drug-indication pairs with no preference for further RCT testing, effect estimates were large [odds ratio (OR): 12.0 (95% confidence interval {CI}: 8.1-17.9)] compared to effect estimates in the 20 drug-indication pairs for which future RCTs were preferred [OR: 4.3 (95% CI 2.8-6.6)], with a significant difference between effects (P = 0.0005). CONCLUSION: Nonrandomized data were used for 7% of EMA drug approvals. Larger effect sizes were associated with greater likelihood of approval based on nonrandomized data alone. We did not find a clear treatment effect threshold for drug approval without RCT evidence.

Treatment targeted at underlying disease versus palliative care in terminally ill patients: a systematic review.

OBJECTIVE: To assess the efficacy of active treatment targeted at underlying disease (TTD)/potentially curative treatments versus palliative care (PC) in improving overall survival (OS) in terminally ill patients. DESIGN: We performed a systematic review and meta-analysis of randomised controlled trials (RCT). Methodological quality of included RCTs was assessed using the Cochrane risk of bias tool. DATA SOURCES: Medline and Cochrane databases were searched, with no language restriction, from inception to 19 October 2016. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Any RCT assessing the efficacy of any active TTD versus PC in adult patients with terminal illness with a prognosis of <6-month survival were eligible for inclusion. RESULTS: Initial search identified 8252 citations of which 10 RCTs (15 comparisons, 1549 patients) met inclusion criteria. All RCTs included patients with cancer. OS was reported in 7 RCTs (8 comparisons, 1158 patients). The pooled results showed no statistically significant difference in OS between TTD and PC (HR (95% CI) 0.85 (0.71 to 1.02)). The heterogeneity between pooled studies was high (I2=62.1%). Overall rates of adverse events were higher in the TTD arm. CONCLUSIONS: Our systematic review of available RCTs in patients with terminal illness due to cancer shows that TTD compared with PC did not demonstrably impact OS and is associated with increased toxicity. The results provide assurance to physicians, patients and family that the patients' survival will not be compromised by referral to hospice with focus on PC.