Adverse events with risankizumab in the real world: postmarketing pharmacovigilance assessment of the FDA adverse event reporting system.

Background: Risankizumab, a humanized IgG1 monoclonal antibody that selectively inhibits IL-23, is currently approved for the treatment of moderate-to-severe plaque psoriasis and Crohn's disease. The real-world safety study of risankizumab in a large- sample population is currently lacking. The aim of this study was to evaluate risankizumab-associated adverse events (AEs) and characterize the clinical priority through the data mining of the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Methods: Disproportionality analyses were performed by calculating the reporting odds ratios (RORs), deemed significant when the lower limit of the 95% confidence interval was greater than 1, to quantify the signals of risankizumab-related AEs from the second quarter (Q2) of 2019 to 2022 Q3. Serious and non-serious cases were compared, and signals were prioritized using a rating scale. Results: Risankizumab was recorded in 10,235 reports, with 161 AEs associated with significant disproportionality. Of note, 37 PTs in at least 30 cases were classified as unexpected AEs, which were uncovered in the drug label, such as myocardial infarction, cataract, pancreatitis, diabetes mellitus, stress, and nephrolithiasis. 74.68%, 25.32%, and 0% PTs were graded as weak, moderate, and strong clinical priorities, respectively. A total of 48 risankizumab-related AEs such as pneumonia, cerebrovascular accident, cataract, loss of consciousness, cardiac disorder, hepatic cirrhosis, and thrombosis, were more likely to be reported as serious AEs. The median TTO of moderate and weak signals related to risankizumab was 115 (IQR 16.75-305) and 124 (IQR 29-301) days, respectively. All of the disproportionality signals had early failure type features, indicating that risankizumab-associated AEs gradually decreased over time. Conclusion: Our study found potential new AE signals and provided valuable evidence for clinicians to mitigate the risk of risankizumab-associated AEs based on an extensive analysis of a large-scale postmarketing international safety database.

The FDA Struggle to Withdraw Makena: Problems With the Accelerated Approval Process.

This Viewpoint discusses the controversy surrounding the FDA's efforts to withdraw Makena from the market and the broader implications for the accelerated approval pathway.

Acute renal failure and cardiac arrhythmias associated with remdesivir use in patients with COVID-19 infections: Analysis using the US FDA adverse event reporting system.

BACKGROUND: Recently, antivirals, including remdesivir, have been repurposed to treat COVID-19 infections. Initial concerns have been raised about the adverse renal and cardiac events associated with remdesivir. OBJECTIVE: This study aimed to analyse the adverse renal and cardiac events associated with remdesivir in patients with COVID-19 infections using the US FDA adverse event reporting system. METHOD: A case/non-case method was used to determine adverse drug events associated with remdesivir as the primary suspect drug between January 1, 2020, and November 11, 2021, for patients with COVID-19 infections. Cases were reports for remdesivir with ≥1 ADEs as preferred terms included in the Medical Dictionary of Regulatory Activities (MedDRA) system organ classes 'Renal and urinary disorders' or 'cardiac' disorders. To measure disproportionality in reporting of ADEs, frequentist approaches, including the proportional reporting ratio (PRR) and reporting odds ratio (ROR), were used. The empirical Bayesian Geometric Mean (EBGM) score and information component (IC) value were calculated using a Bayesian approach. A signal was defined as the lower limit of 95% confidence intervals of ROR ≥ 2, PRR ≥ 2, IC > 0, and EBGM > 1 for ADEs with ≥4 reports. Sensitivity analyses were undertaken by excluding reports for non-Covid indications and medications strongly associated with AKI and cardiac arrhythmias. RESULTS: In the main analysis for remdesivir use in patients with COVID-19 infections, we identified 315 adverse cardiac events comprising 31 different MeDRA PTs and 844 adverse renal events comprising 13 different MeDRA PTs. Regarding adverse renal events, disproportionality signals were noted for "renal failure" (ROR = 2.8 (2.03-3.86); EBGM = 1.92 (1.58-2.31), "acute kidney injury" (ROR = 16.11 (12.52-20.73); EBGM = 2.81 (2.57-3.07), "renal impairment" (ROR = 3.45 (2.68-4.45); EBGM = 2.02 (1.74-2.33). Regarding adverse cardiac events, strong disproportionality signals were noted for "electrocardiogram QT prolonged" (ROR = 6.45 (2.54-16.36); EBGM = 2.04 (1.65-2.51), "pulseless electrical activity" (ROR = 43.57 (13.64-139.20); EBGM = 2.44 (1.74-3.33), "sinus bradycardia" (ROR = 35.86 (11.16-115.26); EBGM = 2.82 (2.23-3.53), "ventricular tachycardia" (ROR = 8.73 (3.55-21.45); EBGM = 2.52 (1.89-3.31). The risk of AKI and cardiac arrythmias were confirmed by sensitivity analyses. CONCLUSION: This hypothesis-generating study identified AKI and cardiac arrhythmias associated with remdesivir use in patients with COVID-19 infections. The relationship between AKI and cardiac arrhythmias should be further investigated using registries or large clinical data to assess the impact of age, genetics, comorbidity, and the severity of Covid infections as potential confounders.

The effect of the COVID-19 pandemic on US Food and Drug Administration-funded clinical trials and natural history studies for rare diseases.

BACKGROUND: Since 1983, the Orphan Product Grants Program, administered by the US Food and Drug Administration, provides funding for clinical trials and natural history studies in rare diseases. The COVID-19 pandemic created new challenges in rare disease product development. This study sought to determine the effects of the pandemic on rare disease studies using data from grantees of this program, and determine lessons learned that can potentially be applied to future trials in rare diseases. METHODS: All grants that were being funded by the Orphan Products Grants Program between March 2020 and March 2021 were included in the study. Data was gathered from grantees and described the effects of the pandemic on multiple aspects of the studies including enrollment, patient follow-up, protocol, and budget. RESULTS: There were 62 grants active during the study period, and of these 54 (87%) were clinical trials and 8 (13%) were natural history studies. 94% of the grantees reported their studies being affected by the COVID-19 pandemic, and the addition of virtual capabilities was reported by 34 (55%) of grantees. CONCLUSIONS: This study suggested two important lessons learned. First, virtual capabilities, when appropriate, can be an important component of trials because they decrease the travel burden on participants and reduce in-person risks, which should increase patient recruitment and retention. Second, building in flexibility in clinical trials is critical in the post-COVID era and could include increasing the use of multi-site trials, clinical networks, and innovative designs and collaborations to speed up trials without compromising study data.

Why did the number of US FDA medical device guidelines begin to rise in the mid-2010s? A perspective.

AREAS COVERED: An initial investigation of US medical device guidelines is presented, with the aid of those of medicines as qualitative comparator. Since the first recorded FDA medical device guideline (February 1975) until the mid-2010s, the number of medical device guidelines has been basically stable, then rapidly rose. EXPERT OPINION: The rise of the COVID-19 pandemic and digital health technologies explains 50% of the upward momentum in guidelines since the mid-2010s. Concomitantly, medical device and medicinal guidelines became moderately correlated. This perspective posits that this trend will continue irrespective of the ebbing pandemic as it is embedded in the concept of 'innovation saltus' - i.e. discrete periods of elevated innovation. A key aspiration of this work is to inspire additional research into this interesting area of regulatory science; namely, examination of guidelines (as proxy measures of regulations) and their influence on innovation.

Remdesivir for COVID-19 and acute kidney injury: disproportionality analysis of data from the U.S. Food and Drug Administration Adverse Event Reporting System.

BACKGROUND: Evidence about remdesivir-associated acute kidney injury (AKI) among patients with novel coronavirus disease 2019 (COVID-19) was controversial. AIM: To investigate the signal of disproportionate reporting of remdesivir-related AKI in COVID-19 patients over time with data from US Food and Drug Administration Adverse Event Reporting System. METHOD: Adverse events in COVID-19 patients reported between April 2020 and September 2022 were included. Reporting odds ratios (RORs) of AKI and renal disorders (a more sensitive definition for AKI) were estimated to compare remdesivir with other medications prescribed in comparable situations of COVID-19. RESULTS: During the entire study period, significant signals were identified for remdesivir-related AKI (ROR 2.00, 95% CI: 1.83-2.18) and renal disorder (ROR 2.35, 95% CI: 2.17-2.54) when compared to all comparable drugs. However, in the third quarter of 2022 (the most recent quarter) signals disappeared as the ROR of AKI was 1.50 (95% CI 0.91-2.45) and ROR of renal disorder was 1.69 (95% CI 1.06-2.70). Number of signals in sensitivity analyses and the proportion of AKI in remdesivir-associated events decreased over time. CONCLUSION: In COVID-19 patients, we observed diminishing signals of remdesivir-associated AKI over time and no significant signal in the most recent quarter, suggesting remdesivir might not be nephrotoxic.

A year in pharmacology: new drugs approved by the US Food and Drug Administration in 2022.

While new drug approvals by the U.S. Food and Drug Administration (FDA) had remained stable or even increased in the first 2 years of the COVID-19 pandemic, the 37 newly approved drugs in 2022 are considerably less than the 53 and 50 new drugs approved in 2020 and 2021, respectively, and less than the rolling 10-year average of 43. As in previous years of this annual review, we assign these new drugs to one of three levels of innovation: first drug against a condition ("first-in-indication"), first drug using a novel molecular mechanism ("first-in-class"), and "next-in-class," i.e., a drug using an already exploited molecular mechanism. We identify two "first-in-indication" (ganaxolon and teplizumab), 20 (54%) "first-in-class," and 17 (46%) "next-in-class" drugs. By treatment area, rare diseases and cancer drugs were once again the most prevalent (partly overlapping) therapeutic areas. Other continuing trends were the use of accelerated regulatory approval pathways and the reliance on biopharmaceuticals (biologics).

Singular secular Kuznets-like period realized amid industrial transformation in US FDA medical devices: a perspective on growth from 1976 to 2020.

INTRODUCTION: Since inception, the United States (US) Food and Drug Administration (FDA) has kept a robust record of regulated medical devices (MDs). Based on these data, can we gain insight into the innovation dynamics of the industry, including the potential for industrial transformation?. AREAS COVERED: Using premarket notifications (PMNs) and approvals (PMAs) data, it is shown that from 1976 to 2020 the total composite (PMN+PMA) metric follows a single secular period: 20.5 years (applications - peak-to-peak: 1992-2012; trough: 2002) and 26.5 years (registrations - peak-to-peak: 1992-2019; trough: 2003), with a peak-to-trough relative percentage difference of 24% and 28%, respectively. Importantly, PMNs and PMAs independently present as an inverse structure. EXPERT OPINION: The evidence suggests that MD innovation is driven by a singular secular Kuznets-like cyclic phenomenon (independent of economic crises) derived from a fundamental shift from simple (PMNs) to complex (PMAs) MDs. Portentously, while the COVID-19 crisis may not affect the overriding dynamic, the anticipated yet significant (~25%) MD innovation drop may be potentially attenuated with attentive measures by MD stakeholders. Limitations of this approach and further thoughts complete this perspective.

Finally, an FDA Approval for an Immunization Against COVID-19: Hope on the Horizon.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) is a respiratory infection known as severe respiratory acute syndrome coronavirus 2 (SARS-CoV-2). The purpose of this manuscript is to review information leading to the Food and Drug Administration (FDA) approval of the Pfizer-BioNTech COVID-19 Vaccine. DATA SOURCES: A literature search was conducted of PubMed and clinicaltrials.gov (August 2018-October 2021) to identify trials related to the FDA approval of Pfizer-BioNTech COVID-19 Vaccine. STUDY SELECTION AND DATA EXTRACTION: Trials included are those the FDA deemed significant and accurate enough to be included in the FDA approval process. Information not recognized by the Centers of Disease Control and Prevention (CDC) nor FDA is omitted to not add to further confusion and misinformation. DATA SYNTHESIS: In persons 16 years or older without evidence of prior SARS-CoV-2 infection, a total of 77 COVID-19 cases (0.39%) in the vaccine group from 7 days onward after the second dose vs 833 (4.1%) in the placebo group (Vaccine efficacy 91.1%; 95% confidence interval [CI]: 88.8-93.1). According the CDC definition of severe infection, there were no severe infections in the vaccine group 7 days and onward after the second dose, compared to 31 (0.15%) in the placebo group (Vaccine efficacy 100%; 95% CI: 87.6-100.0). Relevance to Patient Care and Clinical Practice: Reduction of infection by SARS-COV-2 is a top priority in protecting the health of all people and the official approval of the Pfizer-BioNTech vaccination may improve this goal. CONCLUSIONS: Data available show a high efficacy rate of preventing SARS -CoV-2 with relatively low rates of ADE after full vaccination with Pfizer-BioNTech COVID-19 vaccine.

Questions Remain About What SARS-CoV-2 Variants Should Go Into the Annual COVID-19 Vaccines Proposed by the FDA.

This Medical News story examines the US Food and Drug Administration's proposed plans for an annual COVID-19 vaccination.

Identification of Bradycardia Following Remdesivir Administration Through the US Food and Drug Administration American College of Medical Toxicology COVID-19 Toxic Pharmacovigilance Project.

Importance: The rapid spread and mortality associated with COVID-19 emphasized a need for surveillance system development to identify adverse events (AEs) to emerging therapeutics. Bradycardia is a remdesivir infusion-associated AE listed in the US Food and Drug Administration-approved prescribing information. Objective: To evaluate the magnitude and duration of bradycardic events following remdesivir administration. Design, Setting, and Participants: A multicenter cohort study of patients with recorded heart rate less than 60 beats per minute within 24 hours after administration of a remdesivir dose was conducted between November 23, 2020, and October 31, 2021. Participants included patients hospitalized with COVID-19 at 15 medical centers across the US. Patients excluded had AEs unrelated to bradycardia, AEs in addition to bradycardia, or first onset of bradycardia after 5 remdesivir doses. Exposures: Remdesivir administration. Main Outcomes and Measures: Linear mixed-effect models for the minimum HR before starting remdesivir and within 24 hours of each dose included doses as fixed effects. Baseline covariates were age (≥65 years vs <65 years), sex (male vs female), cardiovascular disease history (yes vs no), and concomitant use of bradycardia-associated medications. The interactions between variables and doses were considered fixed-effects covariates to adjust models. Results: A total of 188 patients were included in the primary analysis and 181 in the secondary analysis. The cohort included 108 men (57.4%); 75 individuals (39.9%) were non-Hispanic White and mean (SD) age was 61.3 (15.4) years. Minimum HR after doses 1 to 5 was lower than before remdesivir. Mean minimum HR was lowest after dose 4, decreasing by -15.2 beats per minute (95% CI, -17.4 to -13.1; P < .001) compared with before remdesivir administration. Mean (SD) minimum HR was 55.6 (10.2) beats per minute across all 5 doses. Of 181 patients included in time-to-event analysis, 91 had their first episode of bradycardia within 23.4 hours (95% CI, 20.1-31.5 hours) and 91 had their lowest HR within 60.7 hours (95% CI, 54.0-68.3 hours). Median time to first bradycardia after starting remdesivir was shorter for patients aged 65 years or older vs those younger than 65 years (18.7 hours; 95% CI, 16.8-23.7 hours vs 31.5 hours; 95% CI, 22.7-39.3 hours; P = .04). Median time to lowest HR was shorter for men vs women (54.2 hours; 95% CI, 47.3-62.0 hours vs 71.0 hours; 95% CI, 59.5-79.6 hours; P = .02). Conclusions and Relevance: In this cohort study, bradycardia occurred during remdesivir infusion and persisted. Given the widespread use of remdesivir, practitioners should be aware of this safety signal.