Purpose The anti-CD19 chimeric antigen receptor T-cell therapy tisagenlecleucel was recently approved to treat relapsed or refractory pediatric acute lymphoblastic leukemia. With a one-time infusion cost of $475,000, tisagenlecleucel is currently the most expensive oncologic therapy. We aimed to determine whether tisagenlecleucel is cost effective compared with currently available treatments. Methods Markov modeling was used to evaluate tisagenlecleucel in pediatric relapsed or refractory acute lymphoblastic leukemia from a US health payer perspective over a lifetime horizon. The model was informed by recent multicenter, single-arm clinical trials. Tisagenlecleucel (under a range of plausible long-term effectiveness) was compared with blinatumomab, clofarabine combination therapy (clofarabine, etoposide, and cyclophosphamide), and clofarabine monotherapy. Scenario and probabilistic sensitivity analyses were used to explore uncertainty. Main outcomes were life-years, discounted lifetime costs, discounted quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (3% discount rate). Results With an assumption of a 40% 5-year relapse-free survival rate, tisagenlecleucel increased life expectancies by 12.1 years and cost $61,000/QALY gained. However, at a 20% 5-year relapse-free survival rate, life-expectancies were more modest (3.8 years) and expensive ($151,000/QALY gained). At a 0% 5-year relapse-free survival rate and with use as a bridge to transplant, tisagenlecleucel increased life expectancies by 5.7 years and cost $184,000/QALY gained. Reduction of the price of tisagenlecleucel to $200,000 or $350,000 would allow it to meet a $100,000/QALY or $150,000/QALY willingness-to-pay threshold in all scenarios. Conclusion The long-term effectiveness of tisagenlecleucel is a critical but uncertain determinant of its cost effectiveness. At its current price, tisagenlecleucel represents reasonable value if it can keep a substantial fraction of patients in remission without transplantation; however, if all patients ultimately require a transplantation to remain in remission, it will not be cost effective at generally accepted thresholds. Price reductions would favorably influence cost effectiveness even if long-term clinical outcomes are modest.

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Background E-values are a recently introduced approach to evaluate confounding in observational studies. We aimed to empirically assess the current use of E-values in published literature. Methods We conducted a systematic literature search for all publications, published up till the end of 2018, which cited at least one of two inceptive E-value papers and presented E-values for original data. For these case publications we identified control publications, matched by journal and issue, where the authors had not calculated E-values. Results In total, 87 papers presented 516 E-values. Of the 87 papers, 14 concluded that residual confounding likely threatens at least some of the main conclusions. Seven of these 14 named potential uncontrolled confounders. 19 of 87 papers related E-value magnitudes to expected strengths of field-specific confounders. The median E-value was 1.88, 1.82, and 2.02 for the 43, 348, and 125 E-values where confounding was felt likely to affect the results, unlikely to affect the results, or not commented upon, respectively. The 69 case-control publication pairs dealt with effect sizes of similar magnitude. Of 69 control publications, 52 did not comment on unmeasured confounding and 44/69 case publications concluded that confounding was unlikely to affect study conclusions. Conclusions Few papers using E-values conclude that confounding threatens their results, and their E-values overlap in magnitude with those of papers acknowledging susceptibility to confounding. Facile automation in calculating E-values may compound the already poor handling of confounding. E-values should not be a substitute for careful consideration of potential sources of unmeasured confounding. If used, they should be interpreted in the context of expected confounding in specific fields.

With pharmaceutical companies shrinking their research departments and exiting out of efforts related to unprofitable diseases, society has become increasingly dependent on academic institutions to perform drug discovery and early-stage translational research. Academic drug discovery and translational research programs assist in shepherding promising therapeutic opportunities through the so-called valley of death in the hope that a successful new drug will result in saved lives, improved health, economic growth, and financial return. We have interviewed directors of 16 such academic programs in the United States and found that these programs and the projects therein face numerous challenges in reaching the clinic, including limited funding, lack of know-how, and lack of a regional drug development ecosystem. If these issues can be addressed through novel industry partnerships, the revision of government policies, and expanded programs in translational education, more effective new therapies are more likely to reach patients in need. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 59 is January 6, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Aims Left ventricular thrombus (LVT) increases the risk of thrombotic events and mortality. Vitamin K antagonists (VKAs) used to treat LVT have several known risks, as a result of which direct oral anticoagulant (DOAC) use has recently increased. We aimed to evaluate the safety and efficacy of DOACs and VKAs in treating LVT. Methods and results We searched PubMed, Embase, Cochrane Library trials, and Web of Science databases for studies published before 19 April 2022, involving DOAC versus VKA treatment for patients with LVT. This meta‐analysis comprised 21 studies (total patients, n = 3172; DOAC group, n = 888; VKA group, n = 2284). A statistically significant reduction in bleeding events was observed in patients on DOACs vs. those on VKAs (risk ratio (RR) = 0.73, P = 0.004). Patients on DOACs residing in North American and European regions and those with ischaemic heart disease (IHD) had a significantly lower risk of bleeding events than patients residing in other regions or those with a different LVT aetiology, respectively (RR = 0.78, P = 0.04; RR = 0.38, P = 0.02; and RR = 0.63, P = 0.009). A statistically significant reduction in stroke in patients on DOACs versus VKAs (RR = 0.72, P = 0.03) was observed, and patients on DOACs residing in North America and those with IHD had a significantly lower risk of stroke (RR = 0.73, P = 0.04, and RR = 0.61, P = 0.03, respectively). Compared with VKAs, DOACs are statistically associated with an increase in LVT resolution at 1 month (RR = 1.96, P = 0.008). No statistical between‐group difference in all‐cause mortality (RR = 0.72, P = 0.05), systemic embolism (RR = 0.87, P = 0.74), stroke or systemic embolism (RR = 0.90, P = 0.50), and LVT resolution at the end of follow‐up (RR = 1.06, P = 0.13) was observed. Conclusions Compared with VKAs, DOACs significantly reduce the risk of bleeding events and stroke in LVT patients, but mortality was similar in both groups. The advantages are apparent not only in patients belonging to the predominantly white residential areas such as North American and European regions but also in patients with LVT due to IHD. DOACs show promising effects in treating LVT compared with VKAs.

Objectives: Ultrasound measured optic nerve sheath diameter is a noninvasive, nonirradiating tool for estimating intracranial hypertension. The objective of this systematic review and meta-analysis is summarization of the current evidence for accuracy of ultrasound measured optic nerve sheath diameter in detecting intracranial hypertension in pediatric patients. Data Sources: Medical subject heading terms were used to search MEDLINE, Embase, Google Scholar, Web of Science, and the Cochrane Library for relevant citations. Publications from January 1, 2000, to June 30, 2019, were included in the search strategy. Study Selection: Studies were included if they involved patients less than 18 years, where ultrasound measured optic nerve sheath diameter was compared to conventional, nonophthalmic tests for intracranial hypertension. Studies were excluded if there was insufficient data to compute a sensitivity/specificity table. Case reports, case series, and manuscripts not published in English were also excluded. Data Extraction: The initial search returned 573 citations. Of these, 57 were selected for review. Data Synthesis: Eleven citations were included in the final meta-analysis. A bivariate random-effects meta-analysis was performed, which revealed a pooled sensitivity for ultrasound measured optic nerve sheath diameter of 93% (95% CI, 74–99%), a specificity of 74% (95% CI, 52–88%), and a diagnostic odds ratio of 39.00 (95% CI, 4.16–365.32). The area under the curve of the hierarchical summary receiver operating characteristic curve was 0.90 (95% CI, 0.87–0.93). Subgroup analyses of the test’s performance evaluating new-onset intracranial hypertension and in comparison to invasively measured intracranial pressure were performed. The test performance in these instances was similar to findings in the primary analysis. Conclusions: We are unable to identify a threshold value in ultrasound measured optic nerve sheath diameter for the determination of intracranial hypertension in children. Even though the ultrasound measured optic nerve sheath diameter measurement is highly sensitive to the presence of increased intracranial pressure, the test has only moderate specificity. Therefore, other confirmatory methods and further investigation is necessary in the clinical care of children. The technique is likely not sufficiently precise for clinical use in the absence of other confirmatory methods, and further investigation is necessary to determine clinical protocols for its use in children.

This meta-analysis suggested that prophylactic μ-opioid agonists fentanyl, remifentanil, sufentanil, and alfentanil could significantly decrease the incidence of EA under sevoflurane anesthesia in children compared to placebo. Considering the limitations of the included studies, more clinical studies are required.