Enabling social listening for cardiac safety monitoring: Proceedings from a drug information association-cardiac safety research consortium cosponsored think tank.

This white paper provides a summary of the presentations and discussions from a think tank on "Enabling Social Listening for Cardiac Safety Monitoring" trials that was cosponsored by the Drug Information Association and the Cardiac Safety Research Consortium, and held at the White Oak headquarters of the US Food and Drug Administration on June 3, 2016. The meeting's goals were to explore current methods of collecting and evaluating social listening data and to consider their applicability to cardiac safety surveillance. Social listening is defined as the act of monitoring public postings on the Internet. It has several theoretical advantages for drug and device safety. First, these include the ability to detect adverse events that are "missed" by traditional sources and the ability to detect adverse events sooner than would be allowed by traditional sources, both by affording near-real-time access to data from culturally and geographically diverse sources. Social listening can also potentially introduce a novel patient voice into the conversation about drug safety, which could uniquely augment understanding of real-world medication use obtained from more traditional methodologies. Finally, it can allow for access to information about drug misuse and diversion. To date, the latter 2 of these have been realized. Although regulators from the Food and Drug Administration and the United Kingdom's Medicines and Healthcare Products Regulatory Agency participated in the think tank along with representatives from industry, academia, and patient groups, this article should not be construed to constitute regulatory guidance.

Adjuvanted (AS03) A/H1N1 2009 Pandemic Influenza Vaccines and Solid Organ Transplant Rejection: Systematic Signal Evaluation and Lessons Learnt.

INTRODUCTION: We investigated a signal of solid organ transplant (SOT) rejection after immunisation with (AS03) A/H1N1 2009 pandemic influenza vaccines. METHODS: Potential immunological mechanisms were reviewed and quantitative analyses were conducted. The feasibility of pharmacoepidemiological studies was explored. RESULTS: Overall results, including data from a pharmacoepidemiological study, support the safety of adjuvanted (AS03) pandemic influenza vaccination in SOT recipients. The regulatory commitment to evaluate the signal through a stepwise investigation was closed in 2014. CONCLUSION: Lessons learned highlight the importance of investigating plausible biological mechanisms between vaccines and potentially associated adverse outcomes, and the importance of selecting appropriate study settings and designs for safety signal investigations.

Social Media Listening for Routine Post-Marketing Safety Surveillance.

INTRODUCTION: Post-marketing safety surveillance primarily relies on data from spontaneous adverse event reports, medical literature, and observational databases. Limitations of these data sources include potential under-reporting, lack of geographic diversity, and time lag between event occurrence and discovery. There is growing interest in exploring the use of social media ('social listening') to supplement established approaches for pharmacovigilance. Although social listening is commonly used for commercial purposes, there are only anecdotal reports of its use in pharmacovigilance. Health information posted online by patients is often publicly available, representing an untapped source of post-marketing safety data that could supplement data from existing sources. OBJECTIVES: The objective of this paper is to describe one methodology that could help unlock the potential of social media for safety surveillance. METHODS: A third-party vendor acquired 24 months of publicly available Facebook and Twitter data, then processed the data by standardizing drug names and vernacular symptoms, removing duplicates and noise, masking personally identifiable information, and adding supplemental data to facilitate the review process. The resulting dataset was analyzed for safety and benefit information. RESULTS: In Twitter, a total of 6,441,679 Medical Dictionary for Regulatory Activities (MedDRA(®)) Preferred Terms (PTs) representing 702 individual PTs were discussed in the same post as a drug compared with 15,650,108 total PTs representing 946 individual PTs in Facebook. Further analysis revealed that 26 % of posts also contained benefit information. CONCLUSION: Social media listening is an important tool to augment post-marketing safety surveillance. Much work remains to determine best practices for using this rapidly evolving data source.

Female gender increases the risk of death during hospitalization for pediatric cardiac surgery.

OBJECTIVES: The study objective was to determine whether gender is a determinant of in-hospital mortality after surgery to repair congenital heart disease in patients aged 20 years or less. Secondary objectives were to determine other factors associated with increased risk of death and whether female gender is associated with increased length of stay or total charges. METHODS: The study included a retrospective cohort consisting of all records indicating cardiac operations within the Healthcare Cost and Utilization Project Kids' Inpatient Database for the year 2000. Logistic regression was used to simultaneously evaluate the effect of gender on the risk of death while adjusting for all other factors being considered. Logistic regression was then used to evaluate possible differences in length of stay or total charges. RESULTS: Female gender was associated with increased risk of in-hospital death when all of the other measured factors were taken into consideration (odds ratio 1.31, 95% confidence interval 1.02-1.69). Other factors that were significantly associated with increased in-hospital mortality after pediatric cardiac surgery included the number of days between admission and operation; African American race; young age (neonates and infants compared with children aged > or =1 year); pulmonary hypertension; and the Norwood operation. There were no significant gender differences in risk-adjusted length of stay or total charges. CONCLUSIONS: In-hospital mortality after pediatric cardiac surgery seems to be associated with patient gender but not with the type of insurance or ability to access higher-volume pediatric facilities or teaching hospitals.

Database size and power to detect safety signals in pharmacovigilance.

Most regulatory agencies and pharmaceutical companies focus the majority of their pharmacovigilance on safety signal identification in large databases. GlaxoSmithKline (GSK) has > 100 drugs marketed worldwide. In order to determine which database has the highest statistical power to detect safety signals in three large global databases, ten GSK marketed drugs were randomly selected for review in the three databases. At the time of data lock, the FDA database (Adverse Event Reporting System [AERS]) contained approximately 6.2 million total records of adverse drug reactions (ADRs). The WHO database (VIGIBASE) contained 7.2 million total records of ADRs. GSK's global safety database (OCEANS) contained approximately 2 million total ADRs for all of its marketed drugs. For the ten drugs selected, there was an average of 7566 reports found in AERS, 8661 reports found in VIGIBASE and 15,496 reports in OCEANS. The information from all three databases was used in pairs (AERS/OCEANS; AERS/VIGIBASE; and OCEANS/VIGIBASE) to calculate power using the maximum likelihood estimation. The OCEANS database contained more ADRs for all 10 drugs than AERS. OCEANS also contained more ADRs for 8/10 drugs than VIGIBASE. The highest statistical power to detect safety signals was determined by the pair of databases which had the greatest number of reports for the given drug. Based on this data, it was concluded that the highest power may be achieved by combining those databases with the most drug-specific data. It is also believe that early safety signal detection should involve the use of multiple large global databases because this permits the use of the largest number of reports for a given drug, and that reliance on a single database may reduce statistical power and diversity of ADRs.

Adverse events after protamine administration following cardiopulmonary bypass in infants and children.

UNLABELLED: We performed this study to determine the incidence of and risk factors for adverse events (AEs) in infants and children after the IV administration of protamine after cardiopulmonary bypass. In a retrospective cohort study, all relevant anesthesia records from a 3-yr period were examined to identify AEs after protamine. The AEs were then grouped into three categories by applying increasingly strict criteria. Among 1249 anesthesia records, there were no documented episodes of isolated or hypotension-associated right-sided cardiac failure or acute pulmonary dysfunction. The incidence of systemic hypotension after protamine was between 1.76% (95% confidence interval [CI], 1.11%-2.65%) and 2.88% (95% CI, 2.03%-3.97%), depending on the strictness of case definition. To identify risk factors, we performed a nested case-control study in which unmatched controls were randomly selected from the parent cohort at a 4:1 ratio to cases. Cases of hypotension after protamine were more likely during operations on girls (odds ratio [OR], 6.47; 95% CI, 1.66-32.8), after larger doses of protamine (OR, 1.88; 95% CI, 1.03-3.63), or after smaller doses of heparin (OR, 0.49; 95% CI, 0.17-0.67). IMPLICATIONS: Systemic hypotension after protamine administration occurred in 1.76%-2.88% of pediatric patients having cardiac surgery. Female sex, larger protamine dose, and smaller heparin dose were each associated with increased risk. The development of protamine alternatives or prophylactic therapies may be useful for reducing the frequency of these events.