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The role and value of statistical contributions in drug development up to the point of health authority approval are well understood. But health authority approval is only a true 'win' if the evidence enables access and adoption into clinical practice. In today's complex and evolving healthcare environment, there is additional strategic evidence generation, communication, and decision support that can benefit from statistical contributions. In this article, we describe the history of medical affairs in the context of drug development, the factors driving post‐approval evidence generation needs, and the opportunities for statisticians to optimize evidence generation for stakeholders beyond health authorities in order to ensure that new medicines reach appropriate patients. [ABSTRACT FROM AUTHOR]

Attempts to examine the root causes of injuries in the construction industry have been largely focused on fatalities and other serious injuries. These efforts were undertaken with the assumption that the root causes of serious injuries could lead to identifying approaches that could prevent the recurrence of similar injuries in the future and that these approaches would also be successful in eliminating many minor injuries. While some injuries may be either minor or serious depending on small differences in worker position, etc., that assumption does not appear to be valid for most injuries. The trends of causes leading to minor injuries are often quite different from those resulting in serious injuries. With this assumption, an examination was conducted to profile nearly 136,000 construction worker injuries, most of which did not result in lost time. Results indicate that these injuries, not resulting in lost time, generally do not fit the profile of injuries that result in fatalities or that are serious. Over half of the injuries in the present study were associated with lacerations (usually of the fingers and hand) and injuries sustained by the lumbar spine, upper extremities, or eyes. The percentage of injuries that involved lacerations was considerably higher for construction than for all other industries. The costs of injuries were found to be quite varied, depending on the part of the body that was injured. DOI: 10.1061/(ASCE)0733-9364(2006)132:3(321) CE Database subject headings: Construction industry; Injuries; Accidents; Occupational safety; Productivity.

Objective To determine the extent to which disease duration, alone or in combination with other baseline clinical and non-clinical factors, explains variations in outcome of tocilizumab initiated in biologic-naïve patients with established RA. Methods In this pooled analysis of phase 3 and 4 clinical trials conducted by the sponsor, predictors of response, including demographics, disease characteristics at baseline (start of tocilizumab dosing) and study characteristics (e.g. patient inclusion criteria, tocilizumab dosing regimen) were evaluated. Response was measured as change from baseline to week 24 in Clinical Disease Activity Index (CDAI) and HAQ–Disability Index (HAQ-DI) scores and as the proportions of patients who experienced ≥50% improvement based on ACR criteria (ACR50) and CDAI remission (≤2.8) rates at week 24. Results Improvements in all outcomes investigated were observed in patients receiving tocilizumab. Although disease duration was statistically significant in the models, it accounted for <2% of variation in CDAI and HAQ-DI score changes from baseline to week 24; baseline CDAI and HAQ-DI values accounted for 32% and 15% of variations, respectively. Doubling of disease duration reduced the odds of achieving an ACR50 response by only 9%, and each additional 5-year period of disease duration decreased the odds of achieving CDAI remission by only 15%. Conclusion RA duration, alone or in combination with other baseline characteristics, had a statistically significant but clinically small effect on the outcomes of tocilizumab initiated in biologic-naïve patients with established RA. [ABSTRACT FROM AUTHOR]

Importance: More than half of patients with acute ischemic stroke have minor neurologic deficits (National Institutes of Health Stroke Scale [NIHSS] score of 0-5) at presentation. Although prior major trials of alteplase included patients with low NIHSS scores, few without clearly disabling deficits were enrolled.Objective: To evaluate the efficacy and safety of alteplase in patients with NIHSS scores of 0 to 5 whose deficits are not clearly disabling.Design, Setting, and Participants: The PRISMS trial was designed as a 948-patient, phase 3b, double-blind, double-placebo, multicenter randomized clinical trial of alteplase compared with aspirin for emergent stroke at 75 stroke hospital networks in the United States. Patients with acute ischemic stroke whose deficits were scored as 0 to 5 on the NIHSS and judged not clearly disabling and in whom study treatment could be initiated within 3 hours of onset were eligible and enrolled from May 30, 2014, to December 20, 2016, with final follow-up on March 22, 2017.Interventions: Participants were randomized to receive intravenous alteplase at the standard dose (0.9 mg/kg) with oral placebo (n = 156) or oral aspirin, 325 mg, with intravenous placebo (n = 157).Main Outcomes and Measures: The primary outcome was the difference in favorable functional outcome, defined as a modified Rankin Scale score of 0 or 1 at 90 days via Cochran-Mantel-Haenszel test stratified by pretreatment NIHSS score, age, and time from onset to treatment. Because of early termination of the trial, prior to unblinding or interim analyses, the plan was revised to examine the risk difference of the primary outcome by a linear model adjusted for the same factors. The primary safety end point was symptomatic intracranial hemorrhage (sICH) within 36 hours of intravenous study treatment.Results: Among 313 patients enrolled at 53 stroke networks (mean age, 62 [SD, 13] years; 144 [46%] women; median NIHSS score, 2 [interquartile range {IQR}, 1-3]; median time to treatment, 2.7 hours [IQR, 2.1-2.9]), 281 (89.8%) completed the trial. At 90 days, 122 patients (78.2%) in the alteplase group vs 128 (81.5%) in the aspirin group achieved a favorable outcome (adjusted risk difference, -1.1%; 95% CI, -9.4% to 7.3%). Five alteplase-treated patients (3.2%) vs 0 aspirin-treated patients had sICH (risk difference, 3.3%; 95% CI, 0.8%-7.4%).Conclusions and Relevance: Among patients with minor nondisabling acute ischemic stroke, treatment with alteplase vs aspirin did not increase the likelihood of favorable functional outcome at 90 days. However, the very early study termination precludes any definitive conclusions, and additional research may be warranted.Trial Registration: ClinicalTrials.gov Identifier: NCT02072226. [ABSTRACT FROM AUTHOR]

ABSTRACT Single‐arm trials (SATs), while not preferred, remain in use throughout the drug development cycle. They may be accepted by regulators in particular contexts (e.g., in oncology or rare diseases) when the potential effects of new treatments are very large and placebo treatment is unethical. However, in the postregulatory space, SATs are common, and perhaps even more poorly suited to address the questions of interest. In this manuscript, we review regulatory and HTA positions on SATs; challenges posed by SATs to address research questions beyond regulators, evolving statistical methods to provide context for SATs, case studies where SATs could and could not address questions of interest, and communication strategies to influence decision making and optimize study design to address evidence needs. [ABSTRACT FROM AUTHOR]

Objectives: Tocilizumab has demonstrated efficacy in managing rheumatoid arthritis (RA) from week 2 onward. This sub-study assessed effects of tocilizumab plus disease-modifying anti-rheumatic drugs (DMARDs) during the first week of therapy., Methods: Rapid Onset and Systemic Efficacy was a 24-week, randomised, double-blind, placebo-controlled, parallel-group trial. Adults with moderate to severe active RA taking DMARDs received tocilizumab 8 mg/kg (or placebo) plus DMARDs every 4 weeks. Data were analysed from the first 62 patients at designated study sites who agreed to clinical evaluation and blood sampling at days 3 and 7 and had C-reactive protein levels ≥1 mg/dl. Outcomes included American College of Rheumatology core data set measures, disease activity score using 28 joints (DAS28) and routine assessment of patient index data 3 (RAPID3) scores., Results: Baseline evaluations were similar between groups (tocilizumab, n=40; placebo, n=22). Patient global assessments of disease activity and pain improved significantly in favour of tocilizumab (mean change from baseline to day 7: -16.2 [tocilizumab], 0.8 [placebo] [p=0.005] and -12.2 [tocilizumab], 1.4 [placebo] [p=0.01], respectively). Physician global assessment of disease activity also improved more with tocilizumab (-15.4 [tocilizumab], -5.6 [placebo] [p=0.05]). Changes from baseline in tender/swollen joint counts, physical function and RAPID3 scores were not significantly different between groups. DAS28 significantly improved with tocilizumab versus placebo at day 7 (-1.16 [tocilizumab], -0.27 [placebo] [p=0.007])., Conclusions: Tocilizumab showed significant improvement in patient-reported disease activity, pain and DAS28 score as early as day 7 after first infusion, earlier than physician-reported measures, which may take longer to manifest.