Effect of the FDA Black Box Suicidality Warnings for Antidepressants on Suicide Rates in the USA

Background: Some authors claimed that the US Food and Drug Administration (FDA) black box warning on treatment-emergent suicidality with antidepressants in adolescents (issued 2004) and young adults (issued 2006) led to an increase of suicides, based on the analyses of ecological data with debatable assumptions about putative changes in suicide rates. Aims: To explore if putative changes in suicide rates in adolescents and young adults at the time of the FDA warnings is a detectable signal in the data or compatible with random fluctuations. Method: We applied different changepoint analyses for adolescent and young adult suicide rates from 1981 to 2019 in the USA. Results: Changepoint analysis did not support a detrimental effect of the FDA black box warnings. The downward trend of suicides reversed several years after the warning in adolescents (2007–2009) and many years before in young adults (1999–2001). Limitations: Our analyses cannot rule out detrimental effects of the FDA warnings. However, even if there was such an effect, it was likely small and indistinguishable from random fluctuations in the available suicide data. Conclusion: There is no detectable change of trend in adolescent or young adult suicide rates in line with a detrimental effect of the FDA black box warnings on treatment-emergent suicidality.

Current progress of fluoroquinolones-increased risk of aortic aneurysm and dissection

Aortic aneurysm (AA) and aortic dissection (AD) are major life-threatening diseases around the world. AA is a localized or diffuse dilation of the aorta, while AD is the separation of the layers creating a false lumen within the aortic wall. Fluoroquinolones (FQ) remain one of the most important kind of antibiotics and have a wider clinical use and broad antibacterial spectrum. FQ were also reported to treat infected AA. The most common adverse events (AEs) of FQ are mild and reversible, like headaches, diarrhea and nausea. Due to FQ-related serious AEs, such as tendonitis and tendon rupture, chondrotoxicity, or retinal detachment, QT-prolongation and dysglycemia, the United States Food and Drug Administration (FDA) issued a black box warning for FQ for systemic use in 2016 and updated warnings for FQ several times since then. Of note, in December 2018, FDA issued several “black box warnings” against FQ with the latest safety announcement warning about an increased risk of ruptures in the aorta blood vessel in certain patients. Recently, many studies have indicated an association between FQ and an increase risk of AA and AD. However, the exact mechanism of FQ-induced AA/AD remains unclear. This review aims to highlight the latest research progress of the alarming association between FQ and AA/AD. Moreover, molecular mechanisms of FQ in increasing risk of AA and AD are explored. Hopefully, this review can provide novel insights into FQ-increased the risk of AA/AD and a starting place for stewardship interventions.

An audit of Black Box Warnings (BBWs) in the United States Food and Drug Administration (US-FDA) database - a five-year analysis

Background: The black-box warning (BBW) is the most serious warning that US-FDA can ask for on a drug’s labelling. BBWs represent key safety concerns uncovered either during dossier review or post-approval. We have conducted the present study with the primary objective of assessing BBWs issued by the US-FDA. Methods: BBW’s were identified on US-FDA’s website from 1st January 2015 to 31st December 2019. Prescribing information was used to identify and characterize BBWs into new and minor/major update on a previous BBW. The therapeutic class of the drug, nature [Biological/New Molecular entity (NME)], formulation type, expected duration of use along with the year of first approval of the molecule with BBWs were evaluated. Results: A total of n = 167 BBWs were issued by FDA of which 53 (31.7%) had major updates, 57(34.1%) had minor updates and 57(34.1%) were new BBWs. A total of 137(82%) of BBWs were with NME’s whereas 30(18%) were with biologics. Drugs for neurology 40(25.5%)had the highest number of BBWs followed by oncology 38(24.2%). Among type of BBWs, cardiovascular risk 31 (15%) were the highest. Conclusion: Practicing physicians need to understand that benefit-risk of a drug is dynamic and keep abreast of new data related to it.

Cardiotoxic safety communications after FDA approval of novel cancer therapies.

e18629 Background: Proliferation of novel anticancer therapies has dramatically improved survival. However, in practice, cardiovascular disease (CVD) events have become an increasing concern. Post-market safety communications by the US Food and Drug Administration (FDA) are a primary source of new safety information for patients and providers. Yet, the prevalence and factors associated with the issuance of CVD warnings among cancer therapies are unknown. Methods: Leveraging the Drugs@FDA database and publicly available FDA drug reviews, we identified all anticancer drugs given new-drug applications from 1998-2018. Characteristics related to approval, including drug class, therapeutic area, priority review status, accelerated approval status, orphan product status, regulatory review times, near-regulatory deadline approval status, and post-market safety events were evaluated. Post-market safety communications were defined as the composite of safety-related drug withdrawals and the issuance of black box label warnings or precautions. CVD was defined as heart failure, hypertension (HTN), coronary disease, myocardial infarction, stroke, thromboembolic disease, arrhythmia/electrocardiographic change, or sudden cardiac death. Multivariable logistic regression was used to assess for characteristics associated with the need for CVD safety communications. Results: Overall, there were 125 novel anticancer therapies, including 24 biologics, 10 immunotherapies, and 48 targeted drugs. There were 177 safety communications (41 black box warnings, 7 withdrawals, 4 dose adjustments, and 84 general warnings). Cardiac safety warnings were issued for 63 (51.2%) of therapies, including 23 (36.5% of all) black box warnings. CVD was the most common reason for a black box warning; Table. Among all CVD warnings, arrhythmias (21.6%) followed by heart failure (13.9%), thromboembolic disease (13.9%), uncontrolled HTN (11.8%), sudden CVD death (9.0%), ischemic disease (6.9%), stroke (4.9%), and other CVD events (12.5%) were found. In a multivariable model, only therapeutic class and prior in-class cardiotoxicity were associated with the issuance of CVD safety communications. Conclusions: Among novel cancer therapies, cardiac safety communications are prevalent.[Table: see text]

Use of social media in detecting drug safety-related new black box warnings, labeling changes, or withdrawals: A scoping review (Preprint)

BACKGROUND Social media has become a new source for obtaining real-world data on adverse drug reactions (ADRs). Many studies have investigated the use of social media to detect early signals of ADRs. However, the trustworthiness of signals derived from social media is questionable. To confirm this, a confirmatory research study using positive control (i.e., new black box warnings, labeling changes, or withdrawals) is required. OBJECTIVE To evaluate the use of social media in detecting new black box warnings, labeling changes, or withdrawals in advance. METHODS This scoping review adhered to the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist. A researcher searched PubMed and EMBASE in January of 2021. Original studies analyzing black box warnings, labeling changes, or withdrawals from social media were selected and the results of the studies were summarized. RESULTS A total of 13 articles were included in this scoping review. Most studies (61.5%) collected data from a single source, and 10 of the 13 studies (76.9%) used specialized healthcare social networks and forums. The analytical methods used in the studies varied considerably. Three studies (23.1%) manually annotated posts, while five (38.5%) adopted machine learning algorithms. Most studies concluded that social media could detect signals seven months to nine years before regulatory authority action. The most recently published paper recommends not using social media for pharmacovigilance, however. Several challenges remain in using social media for pharmacovigilance regarding coverage, data quality, and analytic processing. CONCLUSIONS Social media, along with conventional pharmacovigilance measures, can be used to detect signals associated with new black box warnings, labeling changes, or withdrawals. Further studies are required to advance NLP and mine RWD on social media.

Global publication trends and hotspots of molecular biomarkers in DILI from 1991 to 2020: A 30-year bibliometric analysis

Drug-induced liver injury (DILI) is one of the common adverse drug reactions and the leading cause of drug development attritions, black box warnings, and post-marketing withdrawals. Current biomarkers are suboptimal in detecting DILI and predicting its outcome. This study aimed to quantitatively and qualitatively investigate the research trends on DILI biomarkers using bibliometric analysis. All relevant publications were extracted from the Web of Science database. An online analysis platform of literature metrology, bibliographic item co-occurrence matrix builder, and CiteSpace software were used to analyze the publication trends. CitNetExplorer was used to construct direct citation networks and VOSviewer was used to analyze the keywords and research hotspots. We found a total of 485 publications related to DILI biomarkers published from 1991 to 2020. Toxicological Sciences had been the most popular journal in this field over the past 30 years. The USA maintained a top position worldwide and provided a pivotal influence, followed by China. Among all the institutions, the University of Liverpool was regarded as a leader for research collaboration. Moreover, Professors Paul B. Watkins and Tsuyoshi Yokoi made great achievements in topic area. We analyzed the citation networks and keywords, therefore identified five and six research hotspot clusters, respectively. We considered the publication information regarding different countries/regions, organizations, authors, journals, et al. by summarizing the literature on DILI biomarkers over the past 30 years. Notably, the subject of DILI biomarkers is an active area of research. In addition, the investigation and discovery of novel promising biomarkers such as microRNAs, keratin18, and bile acids will be future developing hotspots.

Off-Label Antipsychotic Prescribing for Persons With Dementia in Assisted Living

Off-label antipsychotic use is contra-indicated for persons with dementia due to lack of efficacy and FDA black box warnings. Yet, residents in assisted living (AL), including those with dementia, are frequently prescribed such medications. If distinct typologies of AL communities exist based on prescribing rates, it might be possible to reduce use. Toward that end, data from 247 AL communities in seven states were analyzed to discern potential unobserved latent classes that differentiate prescribing levels. Results using finite mixture modeling determined a 5-class solution best fit the data, with class-level prescribing rates ranging from 16.9% of residents with dementia to 27.4% (Mean = 18.9%). Bivariate tests found differences across classes by variables related to community structure, medication processes, and resident-case mix (e.g., frequent formal pharmacy review was more likely in communities with higher prescribing). Typologies are useful to identify differences and care and may be useful for quality improvement.