Sensitivity analysis for causality in observational studies for regulatory science

Recognizing the importance of real-world data (RWD) for regulatory purposes, the United States (US) Congress passed the 21st Century Cures Act1 mandating the development of Food and Drug Administration (FDA) guidance on regulatory use of real-world evidence. The Forum on the Integration of Observational and Randomized Data (FIORD) conducted a meeting bringing together various stakeholder groups to build consensus around best practices for the use of RWD to support regulatory science. Our companion paper describes in detail the context and discussion carried out in the meeting, which includes a recommendation to use a causal roadmap for complete pre-specification of study designs using RWD. This article discusses one step of the roadmap: the specification of a procedure for sensitivity analysis, defined as a procedure for testing the robustness of substantive conclusions to violations of assumptions made in the causal roadmap. We include a worked-out example of a sensitivity analysis from a RWD study on the effectiveness of Nifurtimox in treating Chagas disease, as well as an overview of various methods available for sensitivity analysis in causal inference, emphasizing practical considerations on their use for regulatory purposes

Characterization of CD56(–)/CD16(+) natural killer (NK) cells: A highly dysfunctional NK subset expanded in HIV-infected viremic individuals

Natural killer (NK) cells are an important component of the innate immune response against viral infections. NK cell-mediated cytolytic activity is defective in HIV-infected individuals with high levels of viral replication. In the present study, we examined the phenotypic and functional characteristics of an unusual CD56(–)/CD16(+) (CD56(–)) NK subset that is greatly expanded in HIV-viremic individuals. The higher level of expression of inhibitory NK receptors and the lower level of expression of natural cytotoxicity receptors observed in the CD56(–) NK fraction compared with that of CD56(+) NK cells was associated with extremely poor in vitro cytotoxic function of this subset. In addition, the secretion of certain cytokines known to be important in initiating antiviral immune responses was markedly reduced in the CD56(–), as compared with the CD56(+) NK cell subset. These data suggest that the expansion of this highly dysfunctional CD56(–) NK cell subset in HIV-viremic individuals largely accounts for the impaired function of the total NK cell population

Linezolid Trough Concentrations Correlate with Mitochondrial Toxicity-Related Adverse Events in the Treatment of Chronic Extensively Drug-Resistant Tuberculosis

Long-term linezolid use is limited by mitochondrial toxicity-associated adverse events (AEs). Within a prospective, randomized controlled trial of linezolid to treat chronic extensively drug-resistant tuberculosis, we serially monitored the translational competence of mitochondria isolated from peripheral blood of participants by determining the cytochrome c oxidase/citrate synthase activity ratio. We compared this ratio with AEs associated with mitochondrial dysfunction. Linezolid trough concentrations were determined for 38 participants at both 600 mg and 300 mg doses. Those on 600 mg had a significantly higher risk of AE than those on 300 mg (HR 3·10, 95% CI 1·23–7 · 86). Mean mitochondrial function levels were significantly higher in patients before starting linezolid compared to their concentrations on 300 mg (P = 0·004) or 600 mg (P 2 μg/ml developing an AE related to mitochondrial toxicity, whether on 300 mg or 600 mg. Therapeutic drug monitoring may be useful to prevent the development of mitochondrial toxicity associated with long-term linezolid use