Background The efficacy of interleukin-6 receptor blockade in hospitalized patients with coronavirus disease 2019 (Covid-19) who are not receiving mechanical ventilation is unclear. Methods We performed a randomized, double-blind, placebo-controlled trial involving patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, hyperinflammatory states, and at least two of the following signs: fever (body temperature >38°C), pulmonary infiltrates, or the need for supplemental oxygen in order to maintain an oxygen saturation greater than 92%. Patients were randomly assigned in a 2:1 ratio to receive standard care plus a single dose of either tocilizumab (8 mg per kilogram of body weight) or placebo. The primary outcome was intubation or death, assessed in a time-to-event analysis. The secondary efficacy outcomes were clinical worsening and discontinuation of supplemental oxygen among patients who had been receiving it at baseline, both assessed in time-to-event analyses. Results We enrolled 243 patients; 141 (58%) were men, and 102 (42%) were women. The median age was 59.8 years (range, 21.7 to 85.4), and 45% of the patients were Hispanic or Latino. The hazard ratio for intubation or death in the tocilizumab group as compared with the placebo group was 0.83 (95% confidence interval [CI], 0.38 to 1.81; P=0.64), and the hazard ratio for disease worsening was 1.11 (95% CI, 0.59 to 2.10; P=0.73). At 14 days, 18.0% of the patients in the tocilizumab group and 14.9% of the patients in the placebo group had had worsening of disease. The median time to discontinuation of supplemental oxygen was 5.0 days (95% CI, 3.8 to 7.6) in the tocilizumab group and 4.9 days (95% CI, 3.8 to 7.8) in the placebo group (P=0.69). At 14 days, 24.6% of the patients in the tocilizumab group and 21.2% of the patients in the placebo group were still receiving supplemental oxygen. Patients who received tocilizumab had fewer serious infections than patients who received placebo. Conclusions Tocilizumab was not effective for preventing intubation or death in moderately ill hospitalized patients with Covid-19. Some benefit or harm cannot be ruled out, however, because the confidence intervals for efficacy comparisons were wide. (Funded by Genentech; ClinicalTrials.gov number, NCT04356937 .)

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Isolation guidelines for severe acute respiratory syndrome-cornavirus-2 (SARS-CoV-2) are largely derived from data collected prior to emergence of the delta variant. We followed a cohort of ambulatory patients with post-vaccination breakthrough SARS-CoV-2 infections with longitudinal collection of nasal swabs for SARS-CoV-2 viral load quantification, whole genome sequencing, and viral culture. All delta variant infections (10/10, 100%) in our cohort were symptomatic, compared with 64% (9/14) of non-delta variant infections. Symptomatic delta variant breakthrough infections were characterized by higher initial viral load, longer duration of virologic shedding by PCR, greater likelihood of replication-competent virus at early stages of infection, and longer duration of culturable virus compared to non-delta variants. The duration of time since vaccination was also correlated with both duration of PCR positivity and duration of detection of replication-competent virus. Nonetheless, no individuals with symptomatic delta variant infections had replication-competent virus by day 10 after symptom onset or 24 hours after resolution of symptoms. These data support current US Center for Disease Control isolation guidelines and reinforce the importance of prompt testing and isolation among symptomatic individuals with delta variant breakthrough infections. Additional data are needed to evaluate these relationships among asymptomatic and more severe delta variant breakthrough infections.

This study offers evidence to show that PCI audiologists note an SES-related disparity in the field of PCI. Respondents suggest the need for a broad and culturally sensitive effort to both increase access to qualified healthcare professionals and develop approaches that will aid parents in the at-home habilitation process.

IMPORTANCE Brand-name combination drugs can be more expensive than the sum of their components, especially when the constituent products are available as generic medications. The potential savings that could be achieved using generic components is not known.OBJECTIVE To estimate the additional cost to Medicare of prescribing brand-name combination medications instead of generic constituents. DESIGN, SETTING, AND PARTICIPANTSRetrospective analysis for 2011 through 2016 using the Medicare data set of Part D beneficiaries prescribed any of the 1500 medications that accounted for the highest total spending in 2015. Brand-name combination drugs that had identical or therapeutically equivalent generic constituents were included.EXPOSURES Brand-name, oral combination medications with constituents available either as generic drugs or therapeutically equivalent generic substitutes. MAIN OUTCOMES AND MEASURESThe estimated difference between the amount spent by Medicare on brand-name combination drugs and the estimated amount that would have been spent on substitutable generic components.RESULTS Among the 1500 medications evaluated, 29 brand-name combination medications were separated into 3 mutually exclusive categories: constituents available as generic medications at identical doses (n = 20), generic constituents at different doses (n = 3), and therapeutically equivalent generic substitutes (n = 6). For the constituents available as generic medications at identical doses category, total spending by Medicare in 2016 on the brand-name combination products was $303 million and the estimated spending for the generic constituents would have been $68 million, which is an estimated difference of $235 million. For the generic constituents at different doses category, total spending by Medicare in 2016 on the brand-name combination products was $232 million and the estimated spending for the generic constituents would have been $13 million, which is an estimated difference of $219 million. For the therapeutically equivalent generic substitutes category, total spending by Medicare in 2016 on the brand-name combination products was $491 million and the estimated spending for the generic constituents would have been $20 million, which is an estimated difference of $471 million. In 2016, the estimated spending for the generic constituents for these 29 drugs would have been $925 million less than the estimated spending for the brand-name combinations. For the 10 most costly combination products available during the entire study period, the listed Medicare spending could have been an estimated $2.7 billion lower between 2011 and 2016 if the generic constituents had been prescribed. CONCLUSIONS AND RELEVANCEIn 2016, the difference between the amount that the Medicare drug benefit program reported spending on brand-name combination medications and the estimated spending for generic constituents for the same number of doses was $925 million. Promoting generic substitution and therapeutic interchange through prescriber education and more ...

Brand-name drugs, including biologics, have been the primary source of increasing prescription drug spending in the US. Each state has drug product selection laws that regulate whether and how pharmacists can substitute prescriptions for brand-name drugs with more affordable equivalents, either small-molecule generic drugs or interchangeable biologics, but the details of these laws can vary.OBJECTIVE To examine the variation in state drug product selection laws with regard to factors that may affect which version of a drug is dispensed. DESIGN, SETTING, AND PARTICIPANTSA cross-sectional analysis was performed, using a legal database, to obtain information on state laws of all states plus Washington, DC, as they existed on September 1, 2019.EXPOSURES Whether substitution was mandatory or permissive, patient consent was needed prior to substitution, patient notification of substitution was required independent of the drug's packaging, and/or pharmacists were protected from special risk of liability for substitution. MAIN OUTCOMES AND MEASURESFor small-molecule and biologic drugs, descriptive statistics were generated for the 4 exposure variables. In addition, for small-molecule drugs, a generic substitution score with a maximum of 1 point was assigned for each exposure variable (range, 0-4 points), with higher scores indicating regulatory requirements limiting substitution. RESULTSThis cross-sectional analysis of the generic drug substitution regulations in the 50 US states and Washington, DC, found that for small-molecule drugs, 19 states required pharmacists to perform generic substitution; 7 states and Washington, DC, required patient consent; 31 states and Washington, DC, mandated patient notification independent of the drug's packaging, and 24 states did not explicitly protect pharmacists from greater liability. Nine states and Washington, DC, had a generic substitution score for small-molecule drugs of 3 or higher, and 45 states had more stringent requirements for interchangeable biologic substitution, most commonly mandatory physician notification. CONCLUSIONS AND RELEVANCEThe findings of this study suggest that there is a need for optimizing state drug product selection laws to promote generic and interchangeable biologic substitution, which may help improve medication adherence and reduce drug spending.

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