Stroke Risk After COVID-19 Bivalent Vaccination Among US Older Adults.

Importance: In January 2023, the US Centers for Disease Control and Prevention and the US Food and Drug Administration noted a safety concern for ischemic stroke among adults aged 65 years or older who received the Pfizer-BioNTech BNT162b2; WT/OMI BA.4/BA.5 COVID-19 bivalent vaccine. Objective: To evaluate stroke risk after administration of (1) either brand of the COVID-19 bivalent vaccine, (2) either brand of the COVID-19 bivalent plus a high-dose or adjuvanted influenza vaccine on the same day (concomitant administration), and (3) a high-dose or adjuvanted influenza vaccine. Design, Setting, and Participants: Self-controlled case series including 11 001 Medicare beneficiaries aged 65 years or older who experienced stroke after receiving either brand of the COVID-19 bivalent vaccine (among 5 397 278 vaccinated individuals). The study period was August 31, 2022, through February 4, 2023. Exposures: Receipt of (1) either brand of the COVID-19 bivalent vaccine (primary) or (2) a high-dose or adjuvanted influenza vaccine (secondary). Main Outcomes and Measures: Stroke risk (nonhemorrhagic stroke, transient ischemic attack, combined outcome of nonhemorrhagic stroke or transient ischemic attack, or hemorrhagic stroke) during the 1- to 21-day or 22- to 42-day risk window after vaccination vs the 43- to 90-day control window. Results: There were 5 397 278 Medicare beneficiaries who received either brand of the COVID-19 bivalent vaccine (median age, 74 years [IQR, 70-80 years]; 56% were women). Among the 11 001 beneficiaries who experienced stroke after receiving either brand of the COVID-19 bivalent vaccine, there were no statistically significant associations between either brand of the COVID-19 bivalent vaccine and the outcomes of nonhemorrhagic stroke, transient ischemic attack, nonhemorrhagic stroke or transient ischemic attack, or hemorrhagic stroke during the 1- to 21-day or 22- to 42-day risk window vs the 43- to 90-day control window (incidence rate ratio [IRR] range, 0.72-1.12). Among the 4596 beneficiaries who experienced stroke after concomitant administration of either brand of the COVID-19 bivalent vaccine plus a high-dose or adjuvanted influenza vaccine, there was a statistically significant association between vaccination and nonhemorrhagic stroke during the 22- to 42-day risk window for the Pfizer-BioNTech BNT162b2; WT/OMI BA.4/BA.5 COVID-19 bivalent vaccine (IRR, 1.20 [95% CI, 1.01-1.42]; risk difference/100 000 doses, 3.13 [95% CI, 0.05-6.22]) and a statistically significant association between vaccination and transient ischemic attack during the 1- to 21-day risk window for the Moderna mRNA-1273.222 COVID-19 bivalent vaccine (IRR, 1.35 [95% CI, 1.06-1.74]; risk difference/100 000 doses, 3.33 [95% CI, 0.46-6.20]). Among the 21 345 beneficiaries who experienced stroke after administration of a high-dose or adjuvanted influenza vaccine, there was a statistically significant association between vaccination and nonhemorrhagic stroke during the 22- to 42-day risk window (IRR, 1.09 [95% CI, 1.02-1.17]; risk difference/100 000 doses, 1.65 [95% CI, 0.43-2.87]). Conclusions and Relevance: Among Medicare beneficiaries aged 65 years or older who experienced stroke after receiving either brand of the COVID-19 bivalent vaccine, there was no evidence of a significantly elevated risk for stroke during the days immediately after vaccination.

Association between different GLP-1 receptor agonists and gastrointestinal adverse reactions: A real-world disproportionality study based on FDA adverse event reporting system database.

Objective: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have significantly improved clinical effects on glycemic control. However, real-world data concerning the difference in gastrointestinal adverse events (AEs) among different GLP-1 RAs are still lacking. Our study aimed to characterize and compare gastrointestinal AEs among different marketed GLP-1 RAs (exenatide, liraglutide, dulaglutide, lixisenatide, and semaglutide) based on real-world data. Methods: Disproportionality analysis was used to evaluate the association between GLP-1 RAs and gastrointestinal adverse events. Data were extracted from the US FDA Adverse Event Reporting System (FAERS) database between January 2018 and September 2022. Clinical characteristics, the time-to-onset, and the severe proportion of GLP-1 RAs-associated gastrointestinal AEs were further analyzed. Results: A total of 21,281 reports of gastrointestinal toxicity were analyzed out of 81,752 adverse event reports, and the median age of the included patients was 62 (interquartile range [IQR] 54-70) years old. Overall GLP-1 RAs were associated with increased risk of gastrointestinal system disorders (ROR, 1.46; 95% CI, 1.44-1.49), which were further attributed to liraglutide (ROR, 2.39; 95% CI, 2.28-2.51), dulaglutide (ROR, 1.39; 95% CI, 1.36-1.42), and semaglutide (ROR, 3.00; 95% CI, 2.89-3.11). Adverse events uncovered in the labels included gastroesophageal reflux disease, gastritis, bezoar, breath odor, intra-abdominal hematoma, etc. Furthermore, it was observed that semaglutide had the greatest risk of nausea (ROR, 7.41; 95% CI, 7.10-7.74), diarrhea (ROR, 3.55; 95% CI, 3.35-3.77), vomiting (ROR, 6.67; 95% CI, 6.32-7.05), and constipation (ROR, 6.17; 95% CI, 5.72-6.66); liraglutide had the greatest risk of abdominal pain upper (ROR, 4.63; 95% CI, 4.12-5.21) and pancreatitis (ROR, 32.67; 95% CI, 29.44-36.25). Most gastrointestinal AEs tended to occur within one month. Liraglutide had the highest severe rate of gastrointestinal AEs (23.31%), while dulaglutide had the lowest, with a severe rate of 12.29%. Conclusion: GLP-1 RA were significantly associated with gastrointestinal AEs, and the association was further attributed to liraglutide, dulaglutide, and semaglutide. In addition, semaglutide had the greatest risk of nausea, diarrhea, vomiting, constipation, and pancreatitis, while liraglutide had the greatest risk of upper abdominal pain. Our study provided valuable evidence for selecting appropriate GLP-1 RAs to avoid the occurrence of GLP-1 RA-induced gastrointestinal AEs.

Selective publication of antidepressant trials and its influence on apparent efficacy: Updated comparisons and meta-analyses of newer versus older trials.

BACKGROUND: Valid assessment of drug efficacy and safety requires an evidence base free of reporting bias. Using trial reports in Food and Drug Administration (FDA) drug approval packages as a gold standard, we previously found that the published literature inflated the apparent efficacy of antidepressant drugs. The objective of the current study was to determine whether this has improved with recently approved drugs. METHODS AND FINDINGS: Using medical and statistical reviews in FDA drug approval packages, we identified 30 Phase II/III double-blind placebo-controlled acute monotherapy trials, involving 13,747 patients, of desvenlafaxine, vilazodone, levomilnacipran, and vortioxetine; we then identified corresponding published reports. We compared the data from this newer cohort of antidepressants (approved February 2008 to September 2013) with the previously published dataset on 74 trials of 12 older antidepressants (approved December 1987 to August 2002). Using logistic regression, we examined the effects of trial outcome and trial cohort (newer versus older) on transparent reporting (whether published and FDA conclusions agreed). Among newer antidepressants, transparent publication occurred more with positive (15/15 = 100%) than negative (7/15 = 47%) trials (OR 35.1, CI95% 1.8 to 693). Controlling for trial outcome, transparent publication occurred more with newer than older trials (OR 6.6, CI95% 1.6 to 26.4). Within negative trials, transparent reporting increased from 11% to 47%. We also conducted and contrasted FDA- and journal-based meta-analyses. For newer antidepressants, FDA-based effect size (ESFDA) was 0.24 (CI95% 0.18 to 0.30), while journal-based effect size (ESJournals) was 0.29 (CI95% 0.23 to 0.36). Thus, effect size inflation, presumably due to reporting bias, was 0.05, less than for older antidepressants (0.10). Limitations of this study include a small number of trials and drugs-belonging to a single class-and a focus on efficacy (versus safety). CONCLUSIONS: Reporting bias persists but appears to have diminished for newer, compared to older, antidepressants. Continued efforts are needed to further improve transparency in the scientific literature.

Pediatric Drug Development Studies for Familial Hypercholesterolemia Submitted to the US Food and Drug Administration Between 2007 and 2020.

Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder of lipoprotein metabolism that leads to an increased risk of developing atherosclerosis and coronary artery disease. Hypercholesterolemia in pediatric patients is typically due to FH. Treatment of pediatric FH is achieved through lifestyle modifications, lipid-modifying pharmacotherapy, and/or apheresis. The primary objective of this review is to describe the characteristics of clinical trials conducted in pediatric patients with FH with data submitted to the US Food and Drug Administration from 2007 to 2020. Of 10 trials with 8 products in pediatric FH submitted to the Food and Drug Administration, 1 product was studied in both the heterozygous and the homozygous phenotypes, 5 were studied for heterozygous hypercholesterolemia only, and 2 were studied for homozygous familial hypercholesterolemia only. Most of the trials included pediatric patients ≥10 years of age and older. Clinical trial characteristics including the primary efficacy end points between pediatric and adult trials were mostly identical. Many lipid-lowering drugs with novel mechanisms of action have been recently approved or are currently being studied. In summary, the drug treatment of hypercholesterolemia in pediatric patients is expanding beyond the use of statins, and now involves multiple mechanisms of action involving cholesterol metabolism. As younger pediatric patients are diagnosed and treated for heterozygous familial hypercholesterolemia and homozygous familial hypercholesterolemia, optimizing the doses of these agents and safety studies specific to younger pediatric patients will be necessary.

Cardiovascular safety profile of taxanes and vinca alkaloids: 30 years FDA registry experience.

OBJECTIVE: Antimicrotubular agents are among the most commonly used classes of chemotherapeutic agents, but the risk of cardiovascular adverse events (CVAEs) remains unclear. Our objective was to study the CVAEs associated with antimicrotubular agents. METHODS: The Food and Drug Administration's Adverse Event Reporting System was used to study CVAEs in adults from 1990 to 2020. Reported single-agent (only taxane or vinca alkaloid) CVAEs were compared with combination therapy (with at least one of the four major cardiotoxic drugs: anthracycline, HER2Neu inhibitors, tyrosine kinase inhibitors and checkpoint inhibitors) using adjusted polytomous logistic regression. RESULTS: Over 30 years, 134 398 adverse events were reported, of which 18 426 (13.4%) were CVAEs, with 74.1% due to taxanes and 25.9% due to vinca alkaloids. In 30 years, there has been a reduction in the proportion of reported CVAEs for taxanes from 15% to 11.8% (Cochran-Armitage P-trends <0.001) with no significant change in the proportion of reported CVAEs for vinca alkaloids (9.2%-11.7%; P-trends=0.06). The proportion of reported CVAEs was lower in both taxane and vinca alkaloid monotherapy versus combination therapy (reporting OR=0.50 and 0.55, respectively). Anthracyclines and HER2Neu inhibitor combinations with taxanes or vinca alkaloids primarily drove the higher burden of combination CVAEs. Hypertension requiring hospitalisation and heart failure was significantly lower in monotherapy versus combination antimicrotubular agent therapy. CONCLUSIONS: Antimicrotubular agents are associated with CVAEs, especially in combination chemotherapy regimens. Based on this study, we suggest routine cardiovascular assessment of patients with cancer before initiating antimicrotubular agents in combination therapy.

Quantitative systems pharmacology: Landscape analysis of regulatory submissions to the US Food and Drug Administration.

Quantitative systems pharmacology (QSP) has been proposed as a scientific domain that can enable efficient and informative drug development. During the past several years, there has been a notable increase in the number of regulatory submissions that contain QSP, including Investigational New Drug Applications (INDs), New Drug Applications (NDAs), and Biologics License Applications (BLAs) to the US Food and Drug Administration. However, there has been no comprehensive characterization of the nature of these regulatory submissions regarding model details and intended applications. To address this gap, a landscape analysis of all the QSP submissions as of December 2020 was conducted. This report summarizes the (1) yearly trend of submissions, (2) proportion of submissions between INDs and NDAs/BLAs, (3) percentage distribution along the stages of drug development, (4) percentage distribution across various therapeutic areas, and (5) nature of QSP applications. In brief, QSP is increasingly applied to model and simulate both drug effectiveness and safety throughout the drug development process across disease areas.

Factors associated with fatal coronavirus disease 2019 infections among cancer patients in the US FDA Adverse Event Reporting System database.

Aim: To explore factors affecting coronavirus disease 2019 (COVID-19) mortality among cancer patients based on a pharmacovigilance database. Methods: US FDA Adverse Event Reporting System (FAERS) quarterly data extract files were reviewed for quarters two, three and four of 2020 (i.e., April to December). Patients with an indication related to malignancy and a reported COVID-related reaction were selected. Multivariate logistic regression analysis for factors associated with a fatal outcome was conducted. Results: A total of 2708 patients were included. The following factors were associated with fatal COVID-19 infection: older age (odds ratio [OR]: 1.03; 95% CI: 1.01-1.04), male sex (OR: 1.43; 95% CI: 1.07-1.91), non-US report source (OR: 2.46; 95% CI: 1.93-3.13), hematological malignancy (OR: 1.62; 95% CI: 1.28-2.07), potentially immunosuppressive treatment (OR: 1.83; 95% CI: 1.30-2.58) and diagnosis in quarter two versus quarter four (OR: 1.62; 95% CI: 1.27-2.07). Conclusion: Within FAERS reports, cancer patients who are older, males and receiving immunosuppressive treatment and those with hematological malignancies were at a higher risk of death because of COVID-19 infection.

Lay abstract In this study, individuals with a diagnosis of cancer who were older and males and those receiving immunosuppressive treatment seemed to be at a higher risk of a fatal outcome of coronavirus disease 2019 infection.

Characteristics of Cost-effectiveness Studies for Oncology Drugs Approved in the United States From 2015-2020.

Importance: Increasingly, cost-effectiveness analyses are being done to determine the value of rapidly increasing oncology drugs; however, this assumes that these analyses are unbiased. Objective: To analyze the characteristics of cost-effectiveness studies and to determine characteristics associated with whether an oncology drug is found to be cost-effective. Design, Setting, and Participants: This retrospective cross-sectional study included 254 cost-effectiveness analyses for 116 oncology drugs that were approved by the US Food and Drug Administration from 2015 to 2020. Exposures: Each drug was analyzed for the incremental cost-effectiveness ratio per quality-adjusted life year, the funding of the study, the authors' conflict of interest, the threshold of willingness-to-pay, from what country's perspective the analysis was done, and whether a National Institute for Health and Care Excellence cost-effectiveness analysis had been done. Main Outcomes and Measures: The main outcome was the odds of a study concluding that a drug was cost-effective. Results: There were 116 drug approvals with 254 studies and country perspectives. Of the country perspectives, 132 (52%) were from the US. Forty-seven of 78 drugs with cost-effective studies had been shown to improve overall survival, whereas 15 of 38 of drugs without a cost-effectiveness study had been shown to improve overall survival. Having a study funded by a pharmaceutical company was associated with higher odds of a study concluding that a drug was cost-effective than studies without funding (odds ratio, 41.36; 95% CI, 11.86-262.23). Conclusions and Relevance: In this cross-sectional study, pharmaceutical funding was associated with greater odds that an oncology drug would be found to be cost-effective. These findings suggest that simply disclosing potential conflict of interest is inadequate. We encourage cost-effectiveness analyses by independent groups.

Adverse Cardiovascular and Pulmonary Events Associated With Chimeric Antigen Receptor T-Cell Therapy.

BACKGROUND: Pivotal trials of chimeric antigen receptor T-cell (CAR-T) have identified common toxicities but may have been underpowered to detect cardiovascular and pulmonary adverse events (CPAEs). OBJECTIVES: This study sought to investigate CPAEs associated with commercial CD19-directed CAR-T therapy. METHODS: In this retrospective, pharmacovigilance study, the authors used the Food and Drug Administration adverse event reporting system to identify CPAEs associated with axicabtagene-ciloleucel and tisagenlecleucel. The authors evaluated disproportionate reporting by the reporting odds ratio (ROR) and the lower bound of the information component 95% credibility interval (IC025 >0 is deemed significant). Significant associations were further adjusted to age and sex (adj.ROR). RESULTS: The authors identified CAR-T reports of 2,657 patients, including 546 CPAEs (20.5%). CPAEs overlapped with cytokine release syndrome in 68.3% (373 of 546) of the reports. Compared with the full database, CAR-T was associated with overreporting of tachyarrhythmias (n = 74 [2.8%], adj.ROR = 2.78 [95% CI: 2.21-3.51]), cardiomyopathy (n = 69 [2.6%], adj.ROR = 3.51 [2.42-5.09]), pleural disorders (n = 46 [1.7%], adj.ROR = 3.91 [2.92-5.23]), and pericardial diseases (n = 11 [0.4%], adj.ROR = 2.26 [1.25-4.09], all IC025 >0). Venous thromboembolic events (VTEs) were associated only with axicabtagene-ciloleucel therapy (n = 28 [1.6%], adj.ROR = 1.80 [1.24-2.62], IC025 >0). Atrial fibrillation (n = 55) was the leading tachyarrhythmia, followed by ventricular arrhythmias (n = 14). Tachyarrhythmias and VTEs were reported more often following axicabtagene-ciloleucel than tisagenlecleucel in an age- and sex-adjusted model (adj.ROR = 1.82 [1.04-3.18] and adj.ROR = 2.86 [1.18-6.93], respectively). Finally, the fatality rate of CPAEs was 30.9%. CONCLUSIONS: In this largest post-marketing study to date, the authors identified an association between CAR-T and various CPAEs, including tachyarrhythmias, cardiomyopathy, pericardial and pleural disorders, and VTEs. These findings should be considered in the multidisciplinary assessment for and monitoring of CAR-T therapy recipients.

Assessment of Allergic and Anaphylactic Reactions to mRNA COVID-19 Vaccines With Confirmatory Testing in a US Regional Health System.

Importance: As of May 2021, more than 32 million cases of COVID-19 have been confirmed in the United States, resulting in more than 615 000 deaths. Anaphylactic reactions associated with the Food and Drug Administration (FDA)-authorized mRNA COVID-19 vaccines have been reported. Objective: To characterize the immunologic mechanisms underlying allergic reactions to these vaccines. Design, Setting, and Participants: This case series included 22 patients with suspected allergic reactions to mRNA COVID-19 vaccines between December 18, 2020, and January 27, 2021, at a large regional health care network. Participants were individuals who received at least 1 of the following International Statistical Classification of Diseases and Related Health Problems, Tenth Revision anaphylaxis codes: T78.2XXA, T80.52XA, T78.2XXD, or E949.9, with documentation of COVID-19 vaccination. Suspected allergy cases were identified and invited for follow-up allergy testing. Exposures: FDA-authorized mRNA COVID-19 vaccines. Main Outcomes and Measures: Allergic reactions were graded using standard definitions, including Brighton criteria. Skin prick testing was conducted to polyethylene glycol (PEG) and polysorbate 80 (P80). Histamine (1 mg/mL) and filtered saline (negative control) were used for internal validation. Basophil activation testing after stimulation for 30 minutes at 37 °C was also conducted. Concentrations of immunoglobulin (Ig) G and IgE antibodies to PEG were obtained to determine possible mechanisms. Results: Of 22 patients (20 [91%] women; mean [SD] age, 40.9 [10.3] years; 15 [68%] with clinical allergy history), 17 (77%) met Brighton anaphylaxis criteria. All reactions fully resolved. Of patients who underwent skin prick tests, 0 of 11 tested positive to PEG, 0 of 11 tested positive to P80, and 1 of 10 (10%) tested positive to the same brand of mRNA vaccine used to vaccinate that individual. Among these same participants, 10 of 11 (91%) had positive basophil activation test results to PEG and 11 of 11 (100%) had positive basophil activation test results to their administered mRNA vaccine. No PEG IgE was detected; instead, PEG IgG was found in tested individuals who had an allergy to the vaccine. Conclusions and Relevance: Based on this case series, women and those with a history of allergic reactions appear at have an elevated risk of mRNA vaccine allergy. Immunological testing suggests non-IgE-mediated immune responses to PEG may be responsible in most individuals.

Potential Implications of Expanded US Food and Drug Administration Labeling for Sacubitril/Valsartan in the US.

Importance: The US Food and Drug Administration (FDA) expanded labeling for sacubitril/valsartan for use in individuals with chronic heart failure (HF) with left ventricular ejection fraction (LVEF) lower than normal. The population-level implications of implementation of sacubitril/valsartan at higher LVEF ranges is unknown. While the Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction (PARAGON-HF) trial did not meet its primary end point, the trial may provide useful information in projecting expected clinical events among treated individuals. Objective: To quantify newly eligible treatment candidates for sacubitril/valsartan under the expanded FDA labeling and to apply treatment effects and the number needed to treat (NNT) to prevent 1 worsening HF event derived from subgroups of the PARAGON-HF trial who fall under the revised FDA label. Design, Setting, and Participants: Newly eligible treatment candidates were estimated by mapping the LVEF distribution from 559 520 adult patients hospitalized between 2014 and 2019 in the Get With The Guidelines-Heart Failure registry to adults self-identifying with HF in the National Health and Nutrition Examination Survey (2015 to 2018). The NNT with 3 years of treatment for 3 end points of interest (total HF hospitalizations, total HF hospitalizations and cardiovascular death, and total HF hospitalizations and urgent HF visits and cardiovascular death) were estimated from the PARAGON-HF trial. Data were analyzed from February to June 2021. Main Outcomes and Measures: Number of worsening HF events prevented or postponed if eligible patients were treated with sacubitril/valsartan for 3 years. Results: Of an estimated 4 682 098 adults, the mean (SE) age was 66.3 (0.8) years, 1 995 037 (42.6%) were women, and 748 045 (16.0%) were Black. The potential number of adults projected to be newly eligible varied by the definition of FDA labeling of lower than normal LVEF from 643 161 (95% CI, 534 433-751 888; LVEF of 41% to 50%) to 1 838 756 (95% CI, 1 527 911-2 149 601; LVEF of 41% to 60%). In the PARAGON-HF trial, the NNT to prevent a worsening HF event (range, 7 to 12 patients) was consistent irrespective of specific LVEF range selected. Comprehensive implementation of sacubitril/valsartan among newly eligible patients was empirically estimated to prevent up to 69 268 (95% CI, 57 558-80 978) worsening HF events (LVEF of 41% to 50%) to 182 592 (95% CI, 151 725-213 460) worsening HF events (LVEF of 41% to 60%). Conclusions and Relevance: The expanded FDA labeling is positioned to substantially increase the potential HF population eligible for sacubitril/valsartan by up to 1.8 million individuals and has the potential to prevent or postpone as many as 180 000 worsening HF events, depending on the definition of normal LVEF.

Reporting of Death in US Food and Drug Administration Medical Device Adverse Event Reports in Categories Other Than Death.

Importance: In the US, most postmarket medical device safety data are obtained through adverse event reports that are submitted to the US Food and Drug Administration (FDA)'s Manufacturer and User Facility Device Experience (MAUDE) database. Adverse event reports are classified by the reporter as injury, malfunction, death, or other. If the device may have caused or contributed to a death, or if the cause of death is unknown, the FDA requires that the adverse event be reported as a death. Objective: To determine the percentage of medical device adverse event reports submitted to the MAUDE database that were not classified as death even though the patient died. Design, Setting, and Participants: In this study, a natural language processing algorithm was applied to the MAUDE database, followed by manual text review, to identify reports in the injury, malfunction, other or missing categories that included at least 1 term that suggested a patient death, such as patient died or patient expired, from December 31, 1991, to April 30, 2020, for any medical device. Exposures: Manual review of a random sample of 1000 adverse event reports not classified as death and of selected reports for 62 terms that are associated with deaths but were not classified as death. Main Outcomes and Measures: Percentage of adverse event reports in which the patient was said to have died in the narrative section of the report but the reporter classified the report in a category other than death. Results: The terms in the natural language processing algorithm identified 290 141 reports in which a serious injury or death was reported. Of these, 151 145 (52.1%) were classified by the reporter as death and 47.9% were classified as malfunction, injury, other, or missing. For the overall sample, the percentage of reports with deaths that were not classified as deaths was 23% (95% CI, 20%-25%), suggesting that approximately 31 552 reports in our sample had deaths that were classified in other categories. The overall percentage of missed deaths, defined as the percentage of deaths that were classified in other categories, was 17% (95% CI, 16%-19%). Conclusions and Relevance: Many of the findings of this study suggest that many medical device adverse event reports in the FDA's MAUDE database that involved a patient death are classified in categories other than death. As the FDA only routinely reviews all adverse events that are reported as patient deaths, improving the accuracy of adverse event reporting may enhance patient safety.

DPP-4 Inhibitors and Increased Reporting Odds of Bullous Pemphigoid: A Pharmacovigilance Study of the FDA Adverse Event Reporting System (FAERS) from 2006 to 2020.

BACKGROUND: In recent years, an association between dipeptidyl peptidase-4 (DPP-4) inhibitors and bullous pemphigoid has been detected in pharmacovigilance studies in European and Asian countries; however, no pharmacovigilance data have been published yet in the USA. OBJECTIVE: The objective of this study was to examine the relationship between bullous pemphigoid and DPP-4 inhibitors and other oral diabetes mellitus medications in the FDA Adverse Event Reporting System (FAERS). METHODS: Case/non-case analyses were performed in the FAERS using data from 2006 to 2020 to examine the reporting odds ratio (ROR) signal for bullous pemphigoid for all classes of oral diabetes medications. These analyses were performed under multiple conditions to control for bias: (1) comparison to all other drugs in the FAERS; (2) comparison to other diabetes medications; and (3) comparison to all other diabetes medications where only a single agent was implicated. RESULTS: A statistically significant ROR for bullous pemphigoid was found for DPP-4 inhibitors under all conditions: (1) 109.79 (95% confidence interval [CI] 101.61-118.62); (2) 74.46 (95% CI 60.58-91.52); and (3) 35.94 (95% CI 27.91-46.28). A larger signal was seen for non-US Food and Drug Administration (FDA)-approved (anagliptin, vildagliptin, teneligliptin) vs FDA-approved DPP-4 inhibitors (alogliptin, linagliptin, saxagliptin, sitagliptin), likely because of an overestimation of the ROR for non-FDA-approved drugs. The largest signal was seen under conditions 1 and 2 with vildagliptin (1) 1022.83 (95% CI 909.45-1150.35) and (2) 158.84 (95% CI 127.01-198.66) followed by anagliptin (1) 628.63 (95% CI 221.36-1785.24) and (2) 60.64 (95% CI 20.98-175.26), alogliptin, teneligliptin, linagliptin, sitagliptin, and saxagliptin. Under condition 3, the largest signal was seen with linagliptin 122.25 (95% CI 93.96-159.07). Both metformin and the sulfonylureas had a significant ROR under condition 2 [3.42 (95% CI 3.01-3.89) and 2.07 (95% CI 1.66-2.57) respectively]; however, this association was not present under condition 3 as only confounded cases occurred, and a large majority of reported cases had concurrent exposure to a DPP-4 inhibitor. CONCLUSIONS: Our findings support an association between DPP-4 inhibitors and bullous pemphigoid. This association was maintained under controls to limit bias and falsely elevated signal, including controlling for disease state and cases with multiple drug exposures. Non-FDA-approved DPP-4 inhibitors had a larger ROR compared with FDA-approved DPP-4 inhibitors, likely owing to fewer reported adverse effects overall for non-FDA-approved drugs in FAERS.

Assessment of adverse events associated with remdesivir use for coronavirus disease 2019 using real-world data.

Background: Remdesivir has been used for treating patients with moderate to severe coronavirus disease 2019 (COVID-19) although there is conflicting evidence regarding its usefulness. Data regarding its safety largely come from the clinical trials conducted to support its emergency use authorization (EUA). This study aimed to identify the adverse events of remdesivir with disproportionately high reporting using real-world data.Research design and methods: The adverse event reports submitted to the United States Food and Drug Administration Adverse Event Reporting System (FAERS) by health-care professionals for drugs that have received EUA or approved for the treatment of COVID-19 in the US were studied. Adisproportionality analysis was performed to determine adverse events more frequently reported with remdesivir compared with other COVID-19 drugs in the database.Results: Elevated liver enzymes, acute kidney injury, raised blood creatinine levels, bradycardia, cardiac arrest, and death had disproportionately higher reporting with remdesivir as asuspect drug compared with other drugs. There is no significant difference in the reporting of these events based on patient sex or age.Conclusions: Our study confirms the drug label information regarding liver enzyme elevation. The renal and cardiac safety signals identified necessitate reevaluation for potential drug-labeling changes.

Molecular Initiating Events Associated with Drug-Induced Liver Malignant Tumors: An Integrated Study of the FDA Adverse Event Reporting System and Toxicity Predictions.

Liver malignant tumors (LMTs) represent a serious adverse drug event associated with drug-induced liver injury. Increases in endocrine-disrupting chemicals (EDCs) have attracted attention in recent years, due to their liver function-inhibiting abilities. Exposure to EDCs can induce nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, which are major etiologies of LMTs, through interaction with nuclear receptors (NR) and stress response pathways (SRs). Therefore, exposure to potential EDC drugs could be associated with drug-induced LMTs. However, the drug classes associated with LMTs and the molecular initiating events (MIEs) that are specific to these drugs are not well understood. In this study, using the Food and Drug Administration Adverse Event Reporting System, we detected LMT-inducing drug signals based on adjusted odds ratios. Furthermore, based on the hypothesis that drug-induced LMTs are triggered by NR and SR modulation of potential EDCs, we used the quantitative structure-activity relationship platform for toxicity prediction to identify potential MIEs that are specific to LMT-inducing drug classes. Events related to cell proliferation and apoptosis, DNA damage, and lipid accumulation were identified as potential MIEs, and their relevance to LMTs was supported by the literature. The findings of this study may contribute to drug development and research, as well as regulatory decision making.

Thromboembolic events associated with immune checkpoint inhibitors: A real-world study of data from the food and drug administration adverse event reporting system (FAERS) database.

BACKGROUND: Although there have been a few studies reporting thromboembolic events (TEEs) in patients treated with immune checkpoint inhibitors (ICIs), the detailed profile of the TEEs and the prothrombotic effects of ICIs remain mostly unknown. METHODS: Data from January 2004 to December 2019 in the FAERS database were retrieved. We investigated the clinical characteristics of the TEEs and conducted disproportionality analysis by using reporting odds ratios (ROR) to compare ICIs with the full database and other anti-cancer agents. RESULTS: We identified 1855 reports of TEEs associated with ICIs. Affected patients tended to be male (59.68%) and older than 65 (47.12%). The case-fatality rate of the reported TEEs was high (38%). The median time to onset (TTO) of all cases was 42 (interquartile range [IQR] 15-96) days and the median TTO of fatal cases (31 [IQR 13-73] days) was significantly shorter than non-fatal cases (50 [IQR 20-108] days, p = 0.000002). ICIs showed increased risks of VTE (ROR 2.81, 95% CI 2.69-2.95) and ATE (ROR 1.44, 95% CI 1.37-1.52) compared with the full database. Compared with protein kinase inhibitors, ICIs showed an increased risk of VTE (ROR 1.23, 95% CI 1.17-1.29), but only anti-PD-L1 showed an increased risk of cerebral ATE (ROR 1.38, 95% CI 1.08-1.76). Compared with chemotherapy, ICIs showed an increased risk of PE (ROR 1.14, 95% CI 1.07-1.21). CONCLUSIONS: Our study suggested ICIs tend to increase risks of VTE and ATE. The poor clinical outcome and early onset of these events should attract clinical attention.

Systematic analysis of safety profile for darunavir and its boosted agents using data mining in the FDA Adverse Event Reporting System database.

This current investigation was aimed to generate signals for adverse events (AEs) of darunavir-containing agents by data mining using the US Food and Drug Administration Adverse Event Reporting System (FAERS). All AE reports for darunavir, darunavir/ritonavir, or darunavir/cobicistat between July 2006 and December 2019 were identified. The reporting Odds Ratio (ROR), proportional reporting ratio (PRR), and Bayesian confidence propagation neural network (BCPNN) were used to detect the risk signals. A suspicious signal was generated only if the results of the three algorithms were all positive. A total of 10,756 reports were identified commonly observed in hepatobiliary, endocrine, cardiovascular, musculoskeletal, gastrointestinal, metabolic, and nutrition system. 40 suspicious signals were generated, and therein 20 signals were not included in the label. Severe high signals (i.e. progressive extraocular muscle paralysis, acute pancreatitis, exfoliative dermatitis, acquired lipodystrophy and mitochondrial toxicity) were identified. In pregnant women, umbilical cord abnormality, fetal growth restriction, low birth weight, stillbirth, premature rupture of membranes, premature birth and spontaneous abortion showed positive signals. Darunavir and its boosted agents induced AEs in various organs/tissues, and were shown to be possibly associated with multiple adverse pregnant conditions. This study highlighted some novel and severe AEs of darunavir which need to be monitored prospectively.

Characteristics of Clinical Studies Used for US Food and Drug Administration Supplemental Indication Approvals of Drugs and Biologics, 2017 to 2019.

Importance: After US Food and Drug Administration (FDA) approval of a new drug, sponsors can submit additional clinical data to obtain supplemental approval for use for new indications. Objective: To characterize pivotal trials supporting recent supplemental new indication approvals of drugs and biologics by the FDA and to compare them with pivotal trials that supported these therapeutics' original indication approvals. Design, Setting, and Participants: This is a cross-sectional study characterizing pivotal trials supporting supplemental indication approvals by the FDA between 2017 and 2019 and pivotal trials that supported these therapeutics' original indication approvals. Data analysis was performed from August to October 2020. Main Outcomes and Measures: Number and design of pivotal trials supporting both supplemental and original indication approvals. Results: From 2017 to 2019, the FDA approved 146 supplemental indications for 107 therapeutics on the basis of 181 pivotal efficacy trials. The median (interquartile range) number of trials per supplemental indication was 1 (1-1). Most trials used either placebo (77 trials [42.5%; 95% CI, 35.6%-49.8%]) or active comparators (65 trials [35.9%; 95% CI, 29.3%-43.1%]), and most of these multigroup trials were randomized (141 trials [99.3%; 95% CI, 96.0%-100.0%]) and double-blinded (106 trials [74.5%; 95% CI, 66.6%-81.0%]); 80 trials (44.2%; 95 CI, 37.2%-51.5%) used clinical outcomes as the primary efficacy end point. There was no difference between oncology therapies and those approved for other therapeutic areas to have supplemental indication approvals be based on at least 2 pivotal trials (11.5% vs 20.6%; difference, 9.1%; 95% CI, 2.9%-21.0%; P = .10). Similarly, there was no difference in use of randomization (98.3% vs 100.0%; difference, 1.7%; 95% CI, 1.6%-5.0%; P = .43) among multigroup trials, although these trials were less likely to be double-blinded (50.8% vs 92.3%; difference, 41.5%; 95% CI, 27.4%-55.5%; P < .001); overall, these trials were less likely to use either placebo or active comparators (64.9% vs 86.7%; difference, 21.8% 95% CI, 9.8%-33.9%; P < .001) or to use clinical outcomes as their primary efficacy end point (27.5% vs 61.1%; difference, 33.6%; 95% CI, 14.1%-40.9%; P < .001) and were longer (median [interquartile range], 17 [6-48] weeks vs 95 [39-146] weeks). Original approvals were more likely than supplemental indication approvals to be based on at least 2 pivotal trials (44.0% [95% CI, 33.7%-42.6%] vs 15.8% [95% CI, 10.7%-22.5%]; difference, 28.2%; 95% CI, 17.6%-39.6%; P < .001) and less likely to be supported by at least 1 trial of 12 months' duration (27.6% [95% CI, 17.9%-35.0%] vs 54.8% [95% CI, 46.7%-62.6%]; difference, 27.2%; 95% CI, 14.5%-37.8%; P < .001). Pivotal trial designs were otherwise not significantly different. Conclusions and Relevance: These findings suggest that the number and design of the pivotal trials supporting supplemental indication approvals by the FDA varied across therapeutic areas, with the strength of evidence for cancer indications weaker than that for other indications. There was little difference in the design characteristics of the pivotal trials supporting supplemental indication and original approvals.

Methods Used for Pediatric Dose Selection in Drug Development Programs Submitted to the US FDA 2012-2020.

Dosing is a critical aspect of drug development in pediatrics that has led to trial failures and the inability to label the drug for pediatric use by the US Food and Drug Administration. Developing a structured approach for pediatric dose selection requires knowledge of the current approaches and their success or failure. This study describes the current experience with pediatric dosing methods from 2012 to 2020 and had 2 primary objectives: (1) to identify how the initial pediatric dose was selected and (2) to identify the pivotal dosing strategy used to identify the initially selected dose for safety and efficacy for pediatric clinical trials. Through September 2020, a total of 275 pediatric drug development programs were characterized for initial and pivotal dosing strategies. The success rate for labeling for pediatric use was 76.4%. The most common initial dosing strategy was previous experience with the product, followed by allometric scaling and exposure matching with adults. The most common pivotal dosing strategy was titration to target response in 33% of programs, with the second and third most common being pharmacokinetic/pharmacodynamic studies (30%) and exposure matching (20%), respectively. Additionally, about one-half of pediatric programs incorporated model-informed drug development. The emergence of titration to target response may signal a shift toward precision medicine in pediatric patients. Future work in pediatric drug dose selection should move toward the development of a structured pediatric dose selection approach.