Transparency and Innuendo: An Alternative to Reactive Over-Disclosure

Lassman examines the tension between transparency and other public health interests in the context of the FDA\u27s proposed Drug Watch web site. He argues that although the FDA proposal seeks to achieve a laudable goal--the prompt communication of important useful safety information about drug products to physicians and patients-- it fails to properly balance transparency and other legitimate public health interests

A Phase II Study of the Efficacy and Safety of Oral Selinexor in Recurrent Glioblastoma

PURPOSE: Selinexor is an oral selective inhibitor of exportin-1 (XPO1) with efficacy in various solid and hematological tumors. We assessed intra-tumoral penetration, safety, and efficacy of selinexor monotherapy for recurrent glioblastoma. PATIENTS AND METHODS: Seventy-six adults with Karnofsky Performance Status≥60 were enrolled. Patients undergoing cytoreductive surgery received up to three selinexor doses (twice weekly) pre-operatively (Arm A; N=8 patients). Patients not undergoing surgery received 50mg/m(2) (Arm B, N=24), or 60mg (Arm C, N=14) twice weekly, or 80mg once weekly (Arm D; N=30). Primary endpoint was six-month progression-free survival rate (PFS6). RESULTS: Median selinexor concentrations in resected tumors from patients receiving pre-surgical selinexor was 105.4nM (range 39.7-291nM). In Arms B, C, and D, respectively, the PFS6 was 10% (95%CI, 2.79-35.9), 7.7% (95%CI, 1.17-50.6), and 17% (95%CI, 7.78-38.3). Measurable reduction in tumor size was observed in 19 (28%) and RANO-response rate overall was 8.8% (Arm B, 8.3% (95%CI, 1.0-27.0); C:7.7% (95%CI, 0.2-36.0); D:10% (95%CI, 2.1-26.5)), with one complete and two durable partial responses in Arm D. Serious adverse events (AEs) occurred in 26 (34%) patients; one (1.3%) was fatal. The most common treatment-related AEs were fatigue (61%), nausea (59%), decreased appetite (43%) and thrombocytopenia (43%), and were manageable by supportive care and dose modification. Molecular studies identified a signature predictive of response (AUC=0.88). CONCLUSION: At 80mg weekly, single-agent selinexor induced responses and clinically relevant PFS6 with manageable side effects requiring dose reductions. Ongoing trials are evaluating safety and efficacy of selinexor in combination with other therapies for newly diagnosed or recurrent glioblastoma. TRIAL REGISTRATION: ClinicalTrials.gov, NCT0198634

The impact of chemotherapy on cognitive outcomes in adults with primary brain tumors

There is growing recognition that chemotherapy may have short and long term impact on cognitive function of cancer patients. However, the impact of chemotherapy on the cognition of adult patients with primary brain tumor has not been extensively studied. This article will review the evidence for both positive and negative impact of chemotherapy on cognitive function of adult brain tumor patients as well as potential confounding factors

Exploring student-athletes’ perceptions of their psychological readiness to return to sport following a concussion

Athletes returning to sport following a concussion are deemed “ready” once they progress through the return to sport (RTS) steps. However, this process largely overlooks psychological factors involved in returning to sport. We used a constructivist philosophical position to understand 12 (n = 6 females, n = 6 males) formerly concussed Canadian university student-athletes’ perceptions of factors involved in feeling psychologically ready to RTS. Each student-athlete participated in two videoconference interviews (Interview 1: M = 103 min; Interview 2: M = 88 min). We identified six themes from the life-story interviews: confidence, fear, identity, pressure, support, and case-by-case. Subsequently, we used creative nonfiction analysis to write two composite stories depicting the athletes’ experiences returning to sport following a concussion. Pierre-Olivier’s story portrays a second-year university men’s ice hockey player who experienced a successful RTS following a concussion. His story focuses on his feelings of psychological readiness leading up to his first game following medical clearance. Andrea’s story portrays a women’s rugby captain who experienced an unsuccessful RTS following a concussion. Her story depicts a conversation with her doctor regarding medical clearance as well as interactions with a former teammate seeking advice about her own concussion. This study provides insights about the psychological factors experienced by athletes who are attempting to RTS following concussion. Our results highlight a need to better understand and more comprehensively assess the psychological aspects involved in returning to sport following a concussion

Data from: Clinical trial transparency: a reassessment of industry compliance with clinical trial registration and reporting requirements in the United States

Objective: To evaluate the accuracy of a 2015 cross-sectional analysis published in the BMJ Open which reported that pharmaceutical industry compliance with clinical trial registration and results reporting requirements under United States law was suboptimal and varied widely among companies. Design: We performed a re-assessment of the data reported in Miller et al. to evaluate whether statutory compliance analyses and conclusions were valid. Data Sources: Information from the Dryad Digital Repository, ClinicalTrials.gov, Drugs@FDA, and direct communications with sponsors. Main outcome measures: Compliance with the clinical trial registration and results reporting requirements under the Food and Drug Administration Amendments Act (FDAAA). Results: Industry compliance with FDAAA disclosure requirements was notably higher than reported by Miller et al. Among trials subject to FDAAA, Miller et al. reported that, per drug, a median of 67% (middle 50% range: 0–100%) of trials were fully compliant with registration and results reporting requirements. Upon re-analysis of the data, we found that a median of 100% (middle 50% range: 93–100%) of clinical trials for a particular drug fully complied with the law. When looking at overall compliance at the trial level, our re-assessment yields 94% timely registration and 90% timely results reporting among the 49 eligible trials, and an overall FDAAA compliance rate of 86%. Conclusions: The claim by Miller et al. that industry compliance is below legal standards is based on an analysis that relies upon an incomplete dataset and an interpretation of FDAAA that requires disclosure of study results for drugs that have not yet been approved for any indication. Upon re-analysis using a different interpretation of FDAAA that focuses on whether results were disclosed within 30 days of drug approval, we found that industry compliance with U.S. statutory disclosure requirements for the 15 reviewed drugs was consistently high

Comparison of biomarker assays for EGFR:Implications for precision medicine in patients with glioblastoma

PURPOSE: Patients with glioblastoma (GBM) have a poor prognosis and are in desperate need of better therapies. As therapeutic decisions are increasingly guided by biomarkers, and EGFR abnormalities are common in GBM, thus representing a potential therapeutic target, we systematically evaluated methods of assessing EGFR amplification by multiple assays. Specifically, we evaluated correlation between fluorescence in situ hybridization (FISH), a standard assay for detecting EGFR amplification, with other methods. EXPERIMENTAL DESIGN: Formalin-fixed, paraffin-embedded tumor samples were used for all assays. EGFR amplification was detected using FISH (N = 206) and whole exome sequencing (WES, N = 74). EGFR mRNA expression was measured using reverse transcription-polymerase chain reaction (RT-PCR, N = 206) and transcriptome profiling (RNAseq, N = 64). EGFR protein expression was determined by immunohistochemistry (IHC, N = 34). Significant correlations between various methods were determined using Cohen’s kappa (κ = 0.61 – 0.80 defines substantial agreement) or R(2) statistics. RESULTS: EGFR mRNA expression levels by RNAseq and RT-PCR were highly correlated with EGFR amplification assessed by FISH (κ = 0.702). High concordance was also observed when comparing FISH to WES (κ = 0.739). RNA expression was superior to protein expression in delineating EGFR amplification. CONCLUSIONS: Methods for assessing EGFR mRNA expression (RT-PCR, RNAseq) and copy number (WES), but not protein expression (IHC), can be used as surrogates for EGFR amplification (FISH) in GBM. Collectively, our results provide enhanced understanding of available screening options for patients, which may help guide EGFR-targeted therapy approaches