Objectives: Extrapulmonary impacts of chronic obstructive pulmonary disease (COPD) often include sleep disturbance, poor sleep quality, and daytime sleepiness resulting in detrimental impact on patients' overall health-related quality of life (HRQoL). This study evaluated the impact of sleep disturbance on HRQoL in patients with COPD. Methods: Literature searches were performed in biomedical databases until March 2019. Specific search terms identified observational studies assessing HRQoL in COPD that included sleep as a patient-reported outcome (PRO) endpoint. Only full text articles published in English were included. Results: Out of total 1247 abstracts identified for initial screening, 177 were selected for full text review. Based on the inclusion criteria, PRO-related information from 36 studies are analyzed. Sleep disturbances and poor sleep quality was on average prevalent in more than onethird, ranging from 27%-100% of COPD patients.

Objectives: Notoriety bias is defined as "a selection bias in which a case has a greater chance of being reported if the subject is exposed to the studied factor known to cause, thought to cause, or likely to cause the event of interest". This study aimed to determine the existence of notoriety bias in FDA Adverse Event Reporting System (FAERS) database and estimate its impact on signal strength. Methods: Publicly available FAERS data was used for analysis. 31 drugs which had label change/safety alert issued by FDA were considered. These drugs were reviewed four quadrants before and after the safety alert for number of reports, Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR). Wilcoxon signed rank test was used to compare the number of reports and signal strength before and after the alert. Results: There was increased reporting for 11 drugs after the safety alert/label change by FDA. The reporting of 20 drugs decreased or remained unchanged after the safety alert/label change by FDA. Wilcoxon signed rank test showed that there is no statistically significant difference with respect to the number of reports before and after the safety alert (p: 0.330, Z:-0.974). 14 (45.16%) drugs had increase in ROR, while 17 (54.83%) drugs had decrease in ROR after safety alert issued by FDA (p: 0.953, Z:-0.059). 14 (45.16%) drugs had increase in PRR, while 17 (54.83%) drugs had decrease in PRR after safety alert (p: 0.914, Z:-0.108). Conclusions: Although few FDA safety alert/ warnings had strong and immediate impact, many had no impact on reporting of AE and signal strength. This study found that over reporting due to notoriety bias does not exist in the FAERS database and the overall disproportionality in signal estimates is not altered by safety alert.

Objectives: This study aims in the identification of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) associated with vemurafenib using disproportionality analysis of the FDA database of Adverse Event Reporting System (FAERS). Methods: Data were obtained from the public release of data in FAERS. Case/ non-case method was adopted for the analysis of association between vemurafenib use and DRESS. The data mining algorithm used for the analysis was Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR). A value of ROR-1.96SE.1, PRR$2 were considered as positive signal. Results: A total of 7,869 reports for DRESS have been reported in the FDA database. Amongst which 101 reports were associated with vemurafenib. DRESS ranked 49 th among 900 vemurafenib associated adverse drug events. The mean age was 55.87 (95% CI, 52.21-59.52) and female to male ratio was 1.466:1. A positive signal was obtained with ROR: 13.10 and PRR: 13.12. Four deaths were reported and the non-death serious reports included hospitalization, lifethreatening, disability, and other serious events with 61, 11, 2 and 39 reports respectively. Linear regression analysis indicated there was a significant correlation between the PRR and time (R=0.810; p=0.027) and ROR and time (R=0.807; p=0.028). The Log Likelihood ratio for DRESS with vemurafenib was found to be 151.14 and the reporting ratio was 11.11 (Critical value-5.59). Conclusions: A positive signal was observed for vemurafenib associated DRESS, although a causal relation cannot be definitively proved. Health care professionals should be cautious about the possibility of encountering serious adverse events associated with vemurafenib and should be reported to the regulatory authorities.

Objectives: Asthma causes impairments in health-related quality of life (HRQL). The widely used generic HRQL tool, the EQ-5D-5L, is used to evaluate interventions improving HRQL. However, there is not enough information about its suitability in the asthma population. Methods: Data stems from the randomized controlled trial EPRA, offering pulmonary rehabilitation (PR) for the intervention group. We measured HRQL for 371 patients at four time points according to the intervention group: T0 (randomization), T1 (start of PR), T2 (end of PR), and T3 (three months after PR). We measured the generic EQ-5D-5L (utilities and the Visual Analog Scale (VAS)) and the disease specific Asthma Quality of Life Questionnaire (AQLQ). We calculated intraclass correlation (T0-T1), Cohen's d (T2, T3) and regression analysis to evaluate the responsiveness to changes in asthma control, measured with Asthma Control Test (ACT). Results: ICC was 0.82, 0.72 and 0.74 for AQLQ, utilities and VAS respectively. All HRQL tools could differentiate better between well-controlled asthma versus not wellcontrolled asthma, than between not well-controlled asthma and very poorly controlled asthma. AQLQ showed the highest Cohen's d in almost every case. ACT changes were detected by VAS in every period. AQLQ was more responsive for positive changes while the utilities did not appropriately react to changes. Conclusions: The utilities have difficulties to detect changes due to a change in asthma control. This could modify results of health economic evaluations. Therefore, we suggest the use of additional measures (e.g. AQLQ) to provide a comparison.

Objectives: Ipilimumab, an inhibitor of cytotoxic T-lymphocyte antigen 4 (CTLA-4), as a single agent is used in the treatment of unresectable/metastatic melanoma in patients above the age of 12 or as an adjuvant treatment for cutaneous melanoma with regional lymph node involvement. Hypophysitis associated with the use of ipilimumab is established in the past. However, the time of onset of this event is relatively unexplored. The purpose of this study was to examine the onset profile of Ipilimumab Associated Hypophysitis using the FAERS database. Methods: A systematic data mining was performed in the FAERS Database (2011Q2 to 2019Q4). To access the FAERS data, a pharmacovigilance analytical tool named OpenVigil 2.0 was used. The signal strength of ipilimumab induced hypophysitis was computed using Reporting Odds Ratio (ROR). A positive signal was considered to show a value ROR-1.96SE ,1. The Weibull shape parameter (WSP) test was employed to analyze the time-to-onset profile, which is computed using date of eventdrug start date. The time-to-onset profile of ipilimumab induced hypophysitis was defined by shape and scale parameters. Results: A total of 700 reports was found for hypophysitis in FAERS database. Ipilimumab induced hypophysitis was associated with 551 (78.7%) reports. 48% of the reports from males, 30% from females and gender was not mentioned in the rest. The signal strength of ipilimumab induced hypophysitis was 2327.49 (1940.46 -2791.71) which is above the threshold. The median time-to-onset of hypophysitis associated with ipilimumab use was 62 (range: 45-83) days. WSP test indicated early failure-type profile with shape parameter: 0.89 (95% C.I 0.76-1.02) and scale parameter: 97.79 (95% C.I 74.65-127.38). Conclusions: Ipilimumab followed an early failure-type profile, suggesting requirement of close monitoring during first 90 days of treatment. However, due to widely distributed onset data, it is suggestive to monitor patients for hypophysitis throughout ipilimumab treatment.