Postmarketing Surveillance Data Research Articles

Safety and Effectiveness of Ustekinumab for Crohn's Disease in Japanese Post-marketing Surveillance in Biologic-Naive and -Experienced Conriemed.

To present the real-world evidence on the safety and effectiveness of ustekinumab (UST) through 52-week treatment for Crohn's disease (CD) under an analysis of post-market surveillance data in Japan. This prospective, post-marketing surveillance study was conducted in 341 patients from 91 medical facilities in Japan. Patients received UST 90 mg injected subcutaneously once every 12 weeks (or every 8 weeks if patients show weak effectiveness) after an induction dose given intravenously. Clinical response (100-point decrease in Crohn's Disease Activity Index [CDAI] score), clinical remission (CDAI score of <150), steroid-free clinical remission, C-reactive protein, endoscopy, physician global assessment, and adverse drug reactions (ADRs) were evaluated through 52 weeks. The overall rate of clinical remission was 49.2% at week 8 and 56.0% at week 52. The rate of clinical remission in biologic-naive patients was 75.9% and 66.7% at weeks 8 and 52, respectively, whereas the rate in biologic-experienced patients was 41.4% and 52.6% at weeks 8 and 52, respectively. For 52 weeks, the overall incidence of ADRs and serious adverse drug reactions (SADRs) was 11.7% and 6.7%, respectively. The most frequently reported SADRs was worsening of CD (1.8%). In multivariate analysis, ADRs incidence was significantly lower in patients with ileal involvement of CD (odds ratio = 0.25, 95% CI 0.07-0.85, P = .026), although disease location has no association with effectiveness of UST. The present study identified no new safety concerns and effectiveness for CD in Japanese patients treated with UST.

Long-term safety and effectiveness of eculizumab in patients with aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder: a 2-year interim analysis of post-marketing surveillance in Japan.

The terminal complement C5 inhibitor eculizumab is approved in Japan for relapse prevention in aquaporin-4 antibody-positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD) and is undergoing mandatory post-marketing surveillance (PMS) of clinical use. The objective of the study is to assess the real-world, long-term safety and effectiveness of eculizumab in Japanese patients with AQP4+ NMOSD. Regulatory-mandated PMS analysis implemented as an all-case surveillance of all patients with AQP4+ NMOSD who have been treated with eculizumab in Japan since its approval in November 2019. This PMS interim analysis assessed the safety and effectiveness of eculizumab in Japanese patients with AQP4+ NMOSD from November 2019 to April 2022. Of 147 patients treated with eculizumab who consented to publication, 71 had at least one case report form collected and locked at the interim analysis data cut-off, constituting the safety analysis set; three patients from PREVENT (NCT01892345) were excluded from the effectiveness analysis set. Twelve and 10 patients in the safety and effectiveness analysis sets discontinued, respectively. In the safety analysis set, 67/71 patients (94.4%) were female, mean illness duration was 6.8 [standard deviation (SD): 6.2] years, mean age at eculizumab initiation was 50.7 (SD: 13.3) years, and mean eculizumab treatment duration was 44.6 (SD: 23.7) weeks. At diagnosis of NMOSD, 34/71 patients (47.9%) and 35/71 patients (49.3%) in the safety analysis set had symptoms of optic neuritis and transverse myelitis, respectively. In the safety analysis set, 19/71 patients (26.8%) reported adverse events, 10/71 (14.1%) reported adverse drug reactions (ADRs), and 7/71 (9.9%) reported serious ADRs; no meningococcal infections were observed. In the effectiveness analysis set, 64/68 patients (94.1%) were female, mean disease duration was 6.9 (SD: 6.3) years, mean age at eculizumab initiation was 50.6 (SD: 13.2) years, and 27/68 (39.7%) were tested for C5 genetic polymorphism (all negative). In the 2 years before eculizumab, 51/68 patients (75.0%) experienced relapse. Relapse rate was 0.02/patient-year after eculizumab initiation versus 0.74/patient-year in the 2 years before eculizumab. Overall, 37/68 patients (54.4%) were prescribed immunosuppressants in the 6 months before and 19/40 (47.5%) in the 6-12 months after starting eculizumab treatment. The proportion of patients taking >10 mg/day of prednisolone decreased from 45.6% at 24-20 weeks before to 23.1% and 0% at 48-52 and 100-104 weeks after eculizumab, respectively. This article reports interim PMS data for Japanese patients and provides updated real-world evidence for the safety of eculizumab and its effectiveness at preventing relapses in patients with AQP4+ NMOSD. Safety and effectiveness results are consistent with those from PREVENT.

A new platform for post-marketing surveillance and real-world evidence data collection for substance-based medical devices

The recent passage of European Union (EU) Regulation 2017/745 on medical devices (MDs) has improved the classification of MDs and revised their approval process and the post-marketing evaluation of their safety and effectiveness, promoting transparency and post-marketing oversight in Europe. This new regulation can better ensure patient safety and provide new opportunities for therapeutic innovation. In addition, the new regulations include and define MDs made of substances or of combinations of substances (substance-based MDs: SBMDs). The impressive growth of the MD, including SBMDs, that have been marketed over the recent years has likely been a relevant factor fueling this change. MD regulation requires a major effort from both industry and regulatory bodies to comply with its provisions. Manufacturers should produce sufficient clinical evidence that an MD, under normal conditions of use, provides adequate performance and that the foreseeable risks and frequency of adverse events (AEs) have an acceptable minimum rate, taking into account the benefits provided. We describe how we implemented the post-marketing surveillance (PMS) system of SBMDs to properly deal with post-market monitoring and confirmation of safety and performance, including AEs and the benefit–risk evaluation, as required by the 2017/745 Regulation. The two pillars of this novel system are: 1) passive vigilance, i.e., spontaneous reporting and 2) active post-marketing clinical follow-up (PMCF) activities, which systematically gather, record, and analyze real-world data (RWD) on performance, quality, function, use, tolerability, and safety of an MD, collected through a dedicated, structured web platform. Active PMCF is achieved through a process of generation, validation, and administration of digital questionnaires to all stakeholders, i.e., patients, physicians, both general practitioners and specialists, and pharmacists. The technology, potential use, advantages, and limitations of this large source of RWD are also discussed.

Safety and Effectiveness of Etanercept Biosimilar SB4 for Rheumatic Diseases in South Korea: Real-World Post-marketing Surveillance Data.

SB4 is the first approved biosimilar of etanercept, a biologic tumor necrosis factor inhibitor, to treat various autoimmune diseases including axial spondylarthritis (axSpA), rheumatoid arthritis (RA), psoriatic arthritis (PsA), and plaque psoriasis (PsO). This post-marketing surveillance (PMS) study of SB4 investigated safety and effectiveness in routine clinical practice and is part of the drug approval process in Korea. This prospective, multi-center, open-label, observational, phase IV PMS study was designed to enroll patients with axSpA, RA, PsA, and PsO in Korea from September 2015 to September 2019. Both etanercept-naïve patients or patients switched from reference etanercept were included. SB4 was administered weekly via subcutaneous injections using pre-filled syringes. Safety was assessed by the incidence of adverse events (AEs), adverse drug reactions (ADRs) and serious adverse events (SAE). Effectiveness was assessed by the change from baseline of investigator-rated Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in patients with ankylosing spondylitis (AS) and disease activity score-28 (DAS28) in patients with RA. Among 316 enrolled patients, 314 were included in the safety analysis (176 with AS and 138 with RA). The overall incidence of AEs, ADRs and serious AEs were 17.8, 9.9, and 1.3%, respectively. Most AEs were mild (66.7%) or moderate (31.1%) and not related to SB4 (58.9%). Most common AEs were injection site pruritus (1.9%) and injection site rash (1.3%). At week 24, mean disease activity scores significantly decreased compared to baseline in naïve patients with AS and RA (BASDAI 2.7 vs. 6.2, p < 0.0001; DAS28 3.8 vs. 5.7, p < 0.0001) and in switched patients with AS and RA (BASDAI 1.0 vs. 1.3, p = 0.0018; DAS28 2.4 vs. 2.9, p = 0.0893). This first real-world evidence of SB4 from a phase IV PMS study in Korea shows comparable effectiveness to historical SB4 real-world evidence without any new significant safety signals.

Incidence of Tendon Rupture After Collagenase Clostridium Histolyticum Injection for Treatment of Dupuytren Contracture in Adults: A Postmarketing Safety Analysis

Based, in part, on the clinical study reports of tendon rupture events after collagenase clostridium histolyticum (CCH) (Xiaflex, Endo Pharmaceuticals Inc) treatment for Dupuytren contracture (DC), a Risk Evaluation and Mitigation Strategy program was instituted in 2010 by Auxilium Pharmaceuticals (now Endo Pharmaceuticals Inc) to ensure that the benefits of CCH injection outweighed the risks when treating DC. Using the postmarketing surveillance data collected in this program, a retrospective analysis was conducted to evaluate the incidence of flexor tendon rupture after CCH treatment for DC in the clinical practice setting. The Endo Pharmaceuticals Inc safety database was searched for cases of tendon rupture reported between February 2, 2010, and October 8, 2015. Total number of CCH treatments for DC and incidence of tendon rupture were estimated using CCH dosing derived from clinical trial experience (1.7 CCH vials/treatment) or clinical practice evidence (1.08 CCH vials/treatment). Over the 5.8-year surveillance period, 97,609 vials of CCH were distributed for the treatment of DC, equivalent to an estimated total of 57,416 treatments (at 1.7 CCH vials/treatment) or 90,378 treatments (at 1.08 CCH vials/treatment). Although CCH distribution increased during the surveillance period, reports of tendon rupture were infrequent (approximately 13 cases/y; total cases: flexor tendon, n = 57; ligament/pulley, n = 2), corresponding to a 0.10% (1.7 CCH vials/treatment) or 0.06% (1.08 CCH vials/treatment) mean estimated incidence of tendon rupture in patients with DC after CCH treatment. This retrospective analysis showed that flexor tendon rupture occurred infrequently in patients with DC who were treated with CCH in real-world practice settings between 2010 and 2015. On the basis of these findings and other favorable safety evidence, the Risk Evaluation and Mitigation Strategy program requirement for CCH for the treatment of DC was ended by the US Food and Drug Administration in November2016. Therapeutic IV.

Analysis of Reported Adverse Events Related to Over-the-Scope Clips: A MAUDE Database Analysis

Background and AimsOver-the-scope clips (OTSCs) have been increasingly used in the management of bleeding, perforations, fistulae, and anastomotic leaks in the gastrointestinal tract. However, since their Food and Drug Administration (FDA) approval in 2010, data on the adverse events of OTSC systems have been lacking. The aim of our study was to report and analyze adverse events and device failures associated with OTSC systems using the FDA's Manufacturer and User Facility Device Experience (MAUDE) database. MethodsWe analyzed the FDA MAUDE database post-marketing surveillance data from January 2013 through May 2022 on the two OTSC systems available in the United States. ResultsForty medical device reporting claims were found from January 2013 through May 2022. Adverse events were classified as device-related problems and patient-related adverse events. Forty device-related problems were reported, along with 20 device-related adverse events. Most device-related problems were reported in the Padlock defect closure system (n = 23), followed by the Padlock pro clip system (n = 8) and Ovesco OTSC system (n = 9). The most common device-related problem was related to the failure of OTSC deployment (n = 13), followed by material protrusion or extrusion (n = 7). The most common patient adverse events were perforation (n = 4), esophageal laceration (n = 4), bleeding (n = 3), and luminal stenosis (n = 3). All 4 patients required surgical management of the perforation. No deaths related to the use of OTSCs were reported. ConclusionFailure of OTSC deployment and perforation were the most common device-related problem and patient-related adverse event, respectively. As the use of OTSC systems continues to increase, it is important for endoscopists to be mindful of both the common and rare adverse events associated with OTSC use.

INNV-07. TUMOR TREATING FIELDS (TTFIELDS; 200 KHZ) POST-MARKETING SAFETY DATA FROM PATIENTS WITH GLIOBLASTOMA TREATED BETWEEN 2011–2022

Abstract Tumor Treating Fields therapy (TTFields; 200 kHz) is a noninvasive, locoregional, antimitotic treatment approved for newly diagnosed glioblastoma (ndGBM), recurrent (r) GBM, malignant pleural mesothelioma, and is being investigated in additional solid tumors. Approval in GBM was based on results of the phase 3 EF-11 (TTFields monotherapy; rGBM) and EF-14 (TTFields therapy/maintenance temozolomide; ndGBM), which showed clinical benefit without an increase in adverse events (AEs). Here we review post-marketing surveillance (PMS) data from patients with brain tumors who received TTFields therapy over an 11-year period. Unsolicited PMS data from patients with brain tumors who received TTFields therapy between October 2011 and March 2022, were included. Overall 23,822 patients were included in this analysis. Most patients (72%) were from North America; 24% from Europe, Middle East and Africa, and 4% from Japan. Birth year was available for 23,784 patients; of these, the average age at treatment start was 57 years (range: 3–103). Diagnoses were ndGBM (67%), rGBM (27%), astrocytoma (WHO grade 3; 4%) and other (2%). Overall, 71% of patients reported ≥ 1 AE, with the most common being skin reaction (42%), electric (tingling) sensation (14%), heat (warmth) sensation (12%), and seizure (11%). Furthermore, 56% of patients reported AEs possibly related to TTFields therapy, with the most frequently reported being skin reaction (42%), electric sensation (14%) and heat sensation (12%), occurring underneath the arrays. Numbers and types of AEs were comparable between age and diagnosis groups. PMS data from &amp;gt; 23,000 patients with brain tumors show that TTFields therapy (200 kHz) is well-tolerated, consistent with the known safety profile; no new safety signals were identified. TTFields therapy is not associated with systemic toxicity; most common possibly-related AEs are localized dermatologic events that can be managed with appropriate prophylaxis and treatment strategies.

Morphometric analysis of patient-specific 3D-printed acetabular cups: a comparative study of commercially available implants from 6 manufacturers

Background3D printed patient-specific titanium acetabular cups are used to treat patients with massive acetabular defects. These have highly porous surfaces, with the design intent of enhancing bony fixation. Our aim was to characterise these porous structures in commercially available designs.MethodsWe obtained 12 final-production, patient-specific 3D printed acetabular cups that had been produced by 6 manufacturers. High resolution micro-CT imaging was used to characterise morphometric features of their porous structures: (1) strut thickness, 2) the depth of the porous layer, (3) pore size and (4) the level of porosity. Additionally, we computed the surface area of each component to quantify how much titanium may be in contact with patient tissue. Statistical comparisons were made between the designs.ResultsWe found a variability between designs in relation to the thickness of the struts (0.28 to 0.65 mm), how deep the porous layers are (0.57 to 11.51 mm), the pore size (0.74 to 1.87 mm) and the level of porosity (34 to 85%). One manufacturer printed structures with different porosities between the body and flange; another manufacturer had two differing porous regions within the body of the cups. The cups had a median (range) surface area of 756.5 mm2 (348 – 1724).ConclusionsThere is a wide variability between manufacturers in the porous titanium structures they 3D print. We do not currently know whether there is an optimal porosity and how this variability will impact clinically on the integrity of bony fixation; this will become clearer as post market surveillance data is generated.

Patient-related adverse events and device failures associated with commercially available enteral or duodenal self-expanding metal stents: an analysis of the MAUDE database

Duodenal stents are widely used to treat patients with malignant gastric outlet obstruction (MGOO), most commonly from pancreatic cancer. The WallFlex (Boston Scientific, Natick, Mass, USA) and Evolution (Cook Endoscopy, Winston-Salem, NC, USA) duodenal stents are in widespread use for treating MGOO. The objective of this study was to analyze device failures and patient-related adverse events reported to the U.S. Food and Drug Administration (FDA) for these 2 stents. We analyzed postmarketing surveillance data on the WallFlex and Evolution duodenal stents from January 2000 to January 2022 through the FDA's Manufacturer and User Facility Device Experience (MAUDE) database (https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfmaude/search.cfm). One hundred fifty-four MAUDE reports were identified and analyzed, from which 176 device failures and 186 patient-related adverse events were identified. Device-related failures for the WallFlex stent were delivery system failure (15.4%) and failure to activate the stent (13.2%). Device failures for the Evolution stent were failure to activate the stent (16.5%) and delivery system failure (15.3%). Patient-related adverse events for the WallFlex stent were perforation (18.9%), death (6.6%), and hemorrhage (3.8%), whereas patient-related adverse events for the Evolution duodenal stent were obstruction (16.3%), perforation (6.3%), aspiration (3.8%), and fragments of broken delivery system left in the patient (3.8%). Both stents are associated with device failures such as failure to activate the stent, stent migration, and occlusion by tumor growth. Despite high success rates, duodenal stents can be associated with serious device failures and patient-related adverse events.

P.175 Global FKRP registry - the research database for limb girdle muscular dystrophy R9 (2I)

The Global FKRP Registry is an international registry for individuals with conditions caused by mutation of the Fukutin-Related Protein gene (<i>FKRP</i>): limb girdle muscular dystrophy R9 (LGMDR9, formerly LGMD2I) and the congenital muscular dystrophies (MD) MDC1C, Muscle-Eye-Brain Disease and Walker-Warburg Syndrome. The registry seeks to further understanding of the natural history and prevalence of FKRP-related MD and to aid the rapid identification of eligible patients for clinical studies. It disseminates FKRP-relevant information; provides a source of information to academics, industry and healthcare professionals; and supports the FKRP community. Registration is patient-initiated through a secure online portal (www.fkrp-registry.org). Participants give their consent and are invited to complete a questionnaire about their condition. Data is reported by both patients and their healthcare professionals and includes gene mutation, age of onset, presenting symptoms, motor function and muscle strength, respiratory and cardiac function, and medication. In addition, participants are invited to complete validated questionnaires on quality of life (INQoL) and pain (McGill). In recent years, the registry has assisted recruitment to natural history studies and clinical trials in LGMDR9. It has facilitated research by responding to data enquiries and circulating surveys, demonstrating its effectiveness as a repository of patient data, a tool for data collection and assembly of a trial-ready patient cohort. This year, the registry will implement the newly developed TREAT-NMD LGMD Core Dataset. Collection of a shared dataset by individual LGMD patient registries from around the world will enable a larger and potentially more powerful body of data to be collected on this diverse patient cohort. As knowledge of rare neuromuscular conditions increases and advances in the development of potential therapies are made, the registry is centrally placed to help support the accumulation of natural history and post-marketing surveillance data and facilitate recruitment to clinical trials.

S1106 Analysis of Reported Adverse Events Related to Over the Scope Clips: A MAUDE Database Analysis

Introduction: Over-the-scope clips (OTSC) have been increasingly used in the management of bleeding, perforations, fistulae, and anastomotic leaks in the gastrointestinal tract. However, since their Food and Drug Administration (FDA) approval in 2010, data on the adverse events of OTSC systems has been lacking. Our study aims to report and analyze adverse events and device failures associated with OTSC systems using the FDA’s Manufacturer and User Facility Device Experience (MAUDE) database. Methods: We analyzed the post-marketing surveillance data from the FDA MAUDE database of the two OTSC systems available in the United States: The Padlock clip system and the Ovesco OTSC from April 2017 through May 2022. Results: Thirty-six medical device reporting claims were found from May 2017 through May 2022. Adverse events were classified as device-related problems and patient-related adverse events. Thirty-six device-related problems were reported, along with sixteen device-related adverse events (Table). Most device-related problems were reported in the Padlock defect closure system (n=23), followed by the Padlock pro clip system (n=8) and Ovesco OTSC clip system (n=5). The most common device-related problem was related to the failure of deployment of OTSC (n=14), followed by material protrusion or extrusion (n=6). The most common patient adverse events were perforation (n=4), bleeding (n=3), esophageal laceration (n=3) and luminal stenosis (n=2). Three out of four perforations were in the Padlock pro select closure system. All four patients required surgical management of the perforation. No deaths related to the use of OTSC were reported. Conclusion: Using the data from a publicly available database, the overall adverse events from OTSC systems remain low. Failure of OTSC deployment and perforation were the most common device-related problem and patient-related adverse events, respectively. The identification of common adverse events has the potential to optimize device design and patient outcomes. It is important for endoscopists to be mindful of these potential adverse events when using over-the-scope clips. Table 1. - Device-related problems and adverse events Device-related problems Number Failure of OTSC deployment 14 Other 8 Separation problems 3 Detachment of the device 2 Protrusion or extrusion of over the scope clip system 6 Defective device component 2 Failure of positioning of the device 1 Total 36 Patient related- adverse events Number Gastro-gastric fistula 1 Perforation 4 Local trauma 1 Pain 1 Bleeding 3 Pyloric stenosis 1 Colonic stenosis 1 Esophageal laceration 3 Ulcer 1 Total 16

S1162 A Comparison of Technical Failures and Patient-Related Adverse Events Associated With Three Widely Used Mechanical Lithotripters for ERCP: Insights From the FDA MAUDE Database

Introduction: Mechanical lithotripsy is a commonly used, effective method for fragmenting large biliary or pancreatic duct stones. Real-world data on the most commonly reported complications and modes of failure associated with mechanical lithotripters are limited. We analyzed the post-marketing surveillance data from the FDA’s Manufacturer and User Facility Device Experience (MAUDE) database for three commercially available mechanical lithotripters for use during ERCP. Methods: A search of the FDA MAUDE database from January 2010 to October 2021 was conducted for the the following mechanical lithotripters: Trapezoid RX (Boston Scientific, Natick, MA), LithoCrush (Olympus Endoscopy, Center Valley, PA), and the Fusion Lithotripsy Extraction Basket (Cook Endoscopy, Winston Salem NC). Results were compiled and reviewed. Results: 1,128 medical device reports with 2,129 device malfunctions and 205 patient complications were identified. Most device malfunctions were due to guidewire port or sheath failure (n=379, 17.8%), basket entrapment (n=357, 16.8%), and basket tip separation failure (n=315, 14.8%). The most commonly reported adverse events to patients were an additional procedure to remove an entrapped basket (n=170/205, 82.9%), bleeding (n=15/205, 7.3%), and bowel perforation (n=5/205, 2.4%). Conclusion: Findings from the MAUDE database highlight device and patient-related adverse outcomes that should be recognized to improve clinical success and reduce patient risk.

S472 Clinical Adverse Events Associated With Esophageal Stents: A MAUDE Database Analysis

Introduction: Esophageal stents are widely utilized for the treatment of benign and malignant obstructions. However, associated procedural complications are not well described. We aim to investigate post Food and Drug Administration (FDA) approval outcomes associated with esophageal stents. Methods: We analyzed post-marketing surveillance data on esophageal stents from the FDA Manufacturer and User Facility Device Experience (MAUDE) database from January 2015 to December 2021 to report device-related injuries and modes of failure. This database is an open-access platform that receives device reports from mandatory sources, including manufacturers and facilities, as well as, voluntary sources such as healthcare professionals, patients and consumers. These reports allow the FDA to monitor device performance and device-related safety concerns. Results: During the study period, approximately 899 reported cases with 1312 device issues and 303 patient complications were examined. Reported cases included Ultraflex stent (n= 275, 30.6%), Wallflex stent (n= 210, 23.4%), Covered NITI-S stent (n= 144, 16.0%), and Evolution Partially Covered stent (n= 98, 10.9%). The most reported device issues were due to activation, position, or separation failure (n= 597, 45.5%), followed by migration or expulsion of device (n= 120, 9.1%), break (n= 96, 7.3%), difficulty to remove (n= 43, 3.3%), and material deformation (n= 41, 3.1%). A number of reports described an unclassified adverse event without specifying device or operator problem (n= 100, 7.6 %). The most reported patient adverse events were dysphagia or odynophagia (n= 29, 9,6%), followed by death (n= 24, 7.9%), hemorrhage (n= 22, 7.3%), obstruction or occlusion (n= 22, 7.3%), and perforation (n= 17, 5.6%). Conclusion: Our analysis of the FDA MAUDE database revealed a predominance of reported device complications related to activation, positioning, and separation difficulties. Dysphagia or odynophagia represented the most commonly reported patient complication. This database has notable limitations, including limited information on patient comorbidities, detailed endoscopy reports, an absence of operator experience and total volume of procedures performed in the United States. This study provides insight into the most commonly reported complications of esophageal stents that will help inform the risk/benefit conversation with patients and may lead to a more detailed approach on how to mitigate and manage complications.

DISSEMINATED HERPES ZOSTER VIRUS INFECTION FOLLOWING BARICITINIB IN COVID-19

DISSEMINATED HERPES ZOSTER VIRUS INFECTION FOLLOWING BARICITINIB IN COVID-19

34346 Pooled safety analysis of respiratory tract infections, including COVID-19, in psoriasis patients treated with secukinumab

Objective: To assess risk of respiratory tract infections (RTIs) in secukinumab treated psoriasis patients, evaluate potential association of COVID-19 risk factors [age >65, diabetes, obesity (BMI >40), heart and respiratory disease] with RTI incidences and report COVID-19 cases from Periodic Safety Update Report (PSUR: 26-Dec-2019–25-Dec-2020). Methods: Pooled data from clinical trials and postmarketing safety surveillance, including patients who received ≥1 secukinumab dose, were analyzed. RTIs were reported as exposure-adjusted incidence rates (EAIRs) per 100 patient-years. Results: EAIR (95% CI; n) for ‘any RTI’ with secukinumab 150 mg/300 mg/150 mg+300 mg, was 42.1 (39.6–44.8; n = 2117)/47.5 (46.1–48.9; n = 9704)/46.6 (45.3–48.0; n = 11232). EAIR for ‘viral RTI’ at same doses was 7.1 (6.2–8.0)/7.4 (6.9–7.9)/7.3 (6.9–7.7), and for ‘other RTI’ was 34.3 (32.1–36.6)/38.8 (37.5–40.1)/ 37.7 (36.6–38.9). EAIR ratios in obese versus nonobese patients for viral pharyngitis/streptococcal pharyngitis/bacterial sinusitis with secukinumab 150 mg+300 mg were 4.2 (1.2–15.1)/3.4 (1.7–7.0)/6.9 (2.1–22.3), respectively. Strong associations with other COVID-19 risk factors were not observed. Of 952 COVID-19 cases retrieved, outcome was reported in 416 cases: completely recovered (n = 101), recovered with sequelae (n = 7), condition improving (n = 68), unchanged (n = 165), deteriorated (n = 54) and fatal (n = 21). Overall, 221 cases were confounded by risk factors (age >65, comorbidities, or concomitant use of immunosuppressant). Of 21 COVID-19 fatal cases, 14 had risk factors (age >65, comorbidities and smoking) whereas 7 had limited information. Conclusion: RTIs in secukinumab treated psoriasis patients from pooled clinical trials and postmarketing surveillance data were consistent with previous publications. In this analysis, obesity increased the risk for RTIs. COVID-19 cases in the PSUR revealed no new safety signals regarding known risk of ‘infections and infestations.’

Tacrolimus use and renal function in pregnancy with lupus nephritis: Analysis of post-marketing surveillance data in Japan.

Tacrolimus may be administered to pregnant women with lupus nephritis in Japan if considered therapeutically beneficial, but supporting data are limited. We assessed the safety and effectiveness of tacrolimus before, during, and after pregnancy in women with lupus nephritis receiving tacrolimus. This was an ad hoc analysis of data from a post-marketing surveillance study of tacrolimus in patients with lupus nephritis in Japan. Pregnancy outcomes, nephritis status, and adverse events were assessed for up to 2 years postpartum. Data were available for 23 births in 21 patients (two patients had two births each). Tacrolimus for lupus nephritis was continued during 11 births in nine patients (during and after pregnancy) and discontinued in 12 patients (when pregnancy was known or when approaching delivery). Renal function was generally maintained in patients who gave birth while receiving tacrolimus; however, there were cases of increased urine protein and decreased renal function over 2 years. There were no unexpected adverse events/safety concerns. These data from clinical practice suggest that tacrolimus is a valid treatment option for lupus nephritis in fertile women in Japan and, with careful monitoring, pregnant women with lupus nephritis may continue their tacrolimus treatment.

Safety of Tumor Treating Fields (TTFields) therapy in pediatric patients with malignant brain tumors: Post-marketing surveillance data.

There is an unmet need to develop effective and tolerable treatments for pediatric patients with malignant central nervous system tumors. This is especially essential for pediatric patients with aggressive brain tumors such as high-grade gliomas, which have a typical survival rate of under 2 years. Tumor Treating Fields (TTFields) are locoregional, noninvasive electric fields that produce an antimitotic effect on cancerous cells when applied to the skin via arrays. TTFields therapy (200 kHz) is currently approved in adult patients with newly diagnosed glioblastoma (GBM), with temozolomide, and recurrent GBM as monotherapy. Positive preclinical and clinical data have encouraged off-label use of TTFields therapy in pediatric patients with brain tumors, and this study aims to explore the safety of TTFields therapy in pediatric patients (0–18 years of age) based on data from an unsolicited post-marketing surveillance safety database. The real-world data reported here demonstrate that TTFields therapy has a favorable safety profile for pediatric patients with brain tumors, with no new safety signals observed. Findings from this study warrant further research into the efficacy of TTFields therapy, as well as its potential impact on the quality of life in pediatric patients.

Real-world safety of ulinastatin: a post-marketing surveillance of 11,252 patients in China

BackgroundThe safety assessment of ulinastatin can guide clinical practice. The present study aimed to investigate the real-world safety of ulinastatin in China.MethodsThis multicenter study retrospectively analyzed the post-marketing surveillance data of consecutive patients treated with ulinastatin between August 2014 and June 2017 in the general wards and the intensive care units (ICU) of nine hospitals in China. Adverse drug reactions/adverse drug events (ADRs/ADEs) were collected and evaluated in a post-marketing database.ResultsA total of 11,252 consecutive patients were included in the study: 7009 ICU patients and 4243 general ward patients. Eleven patients with ADRs/ADEs were observed, including nine ICU patients and two general ward patients. The clinical manifestations were liver dysfunction (n = 5 ICU cases, n = 1 general case), thrombocytopenia (n = 2 ICU cases, n = 1 general case), leukopenia (n = 1 ICU case), and rash (n = 1 ICU case). During the study period, the drug ADR/ADE rate of ulinastatin injection was 0.98‰ (11/11,252 × 1000‰). Among the 11,252 valid patients, only 327 received ulinastatin in accordance with the drug specifications. After excluding unreasonable drug use, the calculated ADR rate was 3.06‰ (1/327 × 1000‰) (95% confidence interval: 0.0‰-17.1‰). In ICU and general ward patients, the use of other drugs combined with ulinastatin was associated with the occurrence of ADRs/ADEs (100% with ADRs/ADEs vs. 0% in controls, P < 0.001).ConclusionsThe incidence of ADRs/ADEs of ulinastatin is < 5‰. The ADRs/ADEs involved limited organs, mainly the skin, gastrointestinal tract, and blood. In most cases, the ADRs/ADEs gradually alleviated or recovered after drug withdrawal. The inappropriate/off-label use of ulinastatin should be the focus of surveillance.

Comparison of technical failures and patient-related adverse events associated with 3 widely used mechanical lithotripters for ERCP: insights from the U.S. Food and Drug Administration Manufacturer and User Facility Device Experience database

Mechanical lithotripsy is a commonly used, effective method for fragmenting large biliary or pancreatic duct stones. Real-world data on the most commonly reported adverse events and modes of failure associated with mechanical lithotripters are limited. We analyzed the postmarketing surveillance data from the U.S. Food and Drug Administration's Manufacturer and User Facility Device Experience (MAUDE) database for 3 commercially available mechanical lithotripters for use during ERCP. A search of the MAUDE database from January 2010 to October 2021 was conducted for the following mechanical lithotripters: Trapezoid RX (Boston Scientific, Natick, Mass, USA), LithoCrush (Olympus Endoscopy, Center Valley, Pa, USA), and the Fusion Lithotripsy Extraction Basket (Cook Endoscopy, Winston Salem, NC, USA). Results were compiled and reviewed. In total, 1128 medical device reports with 2129 device malfunctions and 205 patient adverse events were identified. Most device malfunctions were because of guidewire port or sheath failure (n= 379, 17.8%), basket entrapment (n= 357, 16.8%), and basket tip separation failure (n= 315, 14.8%). The most commonly reported adverse events to patients were an additional procedure to remove an entrapped basket (170/205, 82.9%), bleeding (15/205, 7.3%), and bowel perforation (5/205, 2.4%). Findings from the MAUDE database highlight device- and patient-related adverse outcomes that should be recognized to improve clinical success and reduce patient risk.

Myelodysplastic Syndrome/Acute Myeloid Leukemia Following the Use of Poly-ADP Ribose Polymerase (PARP) Inhibitors: A Real-World Analysis of Postmarketing Surveillance Data.

Background and purpose: poly-ADP ribose polymerase (PARP) inhibitors show impressive efficacy in a range of tumors. However, concerns about rare and fatal adverse events, including myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) have arisen. The aim of this study was to excavate and evaluate the risk of PARP inhibitors causing MDS and AML based on real-world data from two international pharmacovigilance databases. Methods: We analyzed adverse event (AE) reports of four PARP inhibitors (olaparib, niraparib, rucaparib and talazoparib) associated with MDS and AML from the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) and EudraVigilance (EV) databases between 1 October 2014, and 30 September 2021, including demographic characteristics, fatality and times to onset. Three different data mining algorithms were used to detect the signals of PARP inhibitors associated with MDS and AML. Results: In total, 16,710 and 11,937 PARP inhibitor AE reports were found in the FAERS and EV databases, of which 332 and 349 were associated with MDS and AML, respectively. The median latencies of MDS and AML associated with PARP inhibitors were 211 [interquartile range (IQR) 93.5–491.25] days and 355 (IQR 72.00–483.50) days, respectively. The average fatality rates of MDS and AML caused by the four PARP inhibitors were 39.23 and 45.39%, respectively, in the FAERS database, while those in the EV database were 32.32 and 34.94%, respectively. Based on the criteria used for the three algorithms, a significant disproportionate association was found between PARP inhibitors as a drug class and MDS/AML. Notably, the risk of MDS was much higher than that of AML. Olaparib appeared to have a stronger association with MDS and AML than did other PARP inhibitors. Conclusion: In the real world, PARP inhibitors increase the risk of MDS and AML, which can result in high mortality and tend to occur during long-term use. Our findings provide objective evidence for the postmarketing safety of PARP inhibitors.