Periprocedural to 1-year safety and efficacy outcomes with the Pipeline Embolization Device with Shield technology for intracranial aneurysms: a prospective, post-market, multi-center study.

BACKGROUND: The first and second generations of the Pipeline Embolization Device (PED) have been widely adopted for the treatment of intracranial aneurysms (IAs) due to their high associated occlusion rates and low morbidity and mortality. The objective of this study was to evaluate the safety and effectiveness of the third- generation Pipeline Shield device (PED-Shield) for the treatment of IAs. METHODS: The SHIELD study was a prospective, single-arm, multicenter, post-market, observational study evaluating the PED-Shield device for the treatment of IAs. The primary efficacy endpoint was complete aneurysm occlusion without significant parent artery stenosis or retreatment at 1-year post-procedure and the primary safety endpoint was major stroke in the territory supplied by the treated artery or neurological death. RESULTS: Of 205 subjects who consented across 21 sites, 204 subjects with 204 target aneurysms were ultimately treated (mean age 54.8±12.81 years, 81.4% [166/204] female). Technical success (ie, deployment of the PED-Shield) was achieved in 98.0% (200/204) of subjects with a mean number of 1.1±0.34 devices per subject and a single device used in 86.8% (177/204) of subjects. The primary effectiveness endpoint was met in 71.7% (143/200) of subjects while the primary safety endpoint occurred in six (2.9%) subjects, two (1.0%) of which led to neurological death. CONCLUSIONS: The findings of the SHIELD study support the safety and effectiveness of the PED-Shield for IA treatment, evidenced by high occlusion rates and low rates of neurological complications in the study population. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT02719522.

Acute kidney injury associated with febuxostat and allopurinol: a post-marketing study.

BACKGROUND: For patients with recurrent flares of gout, tophi, urate crystal arthropathy, and renal stones, urate-lowering therapies (ULTs, including allopurinol and febuxostat) are the first-line treatment. Due to the widespread use of these ULTs (especially in patients with impaired renal function), assessment of the associated renal risk is essential. Accordingly, we performed a disproportionality analysis of reported cases of acute renal failure (ARF) associated with allopurinol and febuxostat. METHODS: We carried out a case/non-case study of the World Health Organization's VigiBase® pharmacovigilance database between January 1, 2008, and December 31, 2018. The frequency of reports of ARF as a standardized Medical Dictionary for Regulatory Activities query for allopurinol and febuxostat was compared with that of all other reports for the two drugs and quoted as the reporting odds ratio (ROR) [95% confidence interval (CI)]. The results' stability was assessed in a series of sensitivity analyses (notably after the exclusion of putative competing drugs). RESULTS: Among 3509 "suspected drug" notifications for febuxostat and 18,730 for allopurinol, we identified respectively 317 and 1008 cases of ARF. Acute renal failure was reported significantly more frequently for febuxostat and allopurinol than for other drugs (ROR [95%CI] 5.67 [5.05-6.36] and 3.25 [3.05-3.47], respectively). For both drugs, the ROR was higher in women than in men, respectively 11.60 [9.74-13.82] vs. 3.14 [2.69-3.67] for febuxostat and 4.45 [4.04-4.91] vs. 2.29 [2.11-2.50] for allopurinol. The sensitivity analyses confirmed the disproportionality for these two ULTs. CONCLUSIONS: Acute renal failure was reported respectively 5.7 and 3.3 times more frequently for febuxostat and for allopurinol than for other drugs. Due to the potential consequences of ARF, physicians should take account of this disproportionality signal when prescribing the ULTs febuxostat and allopurinol.

Analysis of Ornidazole Injection in Clinical Use at Post-marketing Stage by Centralized Hospital Monitoring System.

This study aims to analyze the clinical use of ornidazole injection at the post-marketing stage by centralized hospital monitoring system method, and investigate its widespread use in patients, in order to regulate and guide the rational drug use, improve the drug specificity and provide a basis for drug therapy. The study adopts a prospective, multi-center, large sample size, centralized hospital monitoring system. We selected five leading hospitals in Hubei province, and observed the inpatients who received the ornidazole injection from July 1, 2015 to October 31, 2015. The basic information of patients was recorded, as well as the drug use and adverse events. The statistical analysis was performed based on these data. A total of 4396 individuals were enrolled in this study, most of them were middle-aged female patients and the ornidazole injection was mainly used as prophylactic prior to surgery to prevent the infections, and surgical treatment of anaerobic infections, abdominal infections and pelvic infections. The irrational drug use existed mainly in the prescribing and administration process, including unreasonable dosing frequency, rapid intravenous drip speed and extended duration of drug use. Eleven cases of adverse reactions were collected during the monitoring, incidence rate of adverse reactions was 2.5‰; adverse drug reactions occurred within 30 min. The study results fully reflected the usage of ornidazole injection in the real world. Based on the study, we calculated the adverse reaction incidence of ornidazole and identified the risk factors which may affect the safety of ornidazole injection. Study results strongly recommend that the manufacturers should publish standards for inpatient use and doctors should prescribe with caution accordingly.

Long-term safety of secukinumab in patients with moderate-to-severe plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis: integrated pooled clinical trial and post-marketing surveillance data.

BACKGROUND: Secukinumab, a fully human immunoglobulin G1-kappa monoclonal antibody that directly inhibits interleukin (IL)-17A, has been shown to have robust efficacy in the treatment of moderate-to-severe psoriasis (PsO), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) demonstrating a rapid onset of action and sustained long-term clinical responses with a consistently favorable safety profile in multiple Phase 2 and 3 trials. Here, we report longer-term pooled safety and tolerability data for secukinumab across three indications (up to 5 years of treatment in PsO and PsA; up to 4 years in AS). METHODS: The integrated clinical trial safety dataset included data pooled from 21 randomized controlled clinical trials of secukinumab 300 or 150 or 75 mg in PsO (14 Phase 3 trials and 1 Phase 4 trial), PsA (3 Phase 3 trials), and AS (3 Phase 3 trials), along with post-marketing safety surveillance data with a cut-off date of June 25, 2017. Adverse events (AEs) were reported as exposure-adjusted incident rates (EAIRs) per 100 patient-years. Analyses included all patients who received ≥ 1 dose of secukinumab. RESULTS: A total of 5181, 1380, and 794 patients from PsO, PsA, and AS clinical trials representing secukinumab exposures of 10,416.9, 3866.9, and 1943.1 patient-years, respectively, and post-marketing data from patients with a cumulative exposure to secukinumab of ~ 96,054 patient-years were included in the analysis. The most frequent AE was upper respiratory tract infection. EAIRs across PsO, PsA, and AS indications were generally low for serious infections (1.4, 1.9, and 1.2, respectively), Candida infections (2.2, 1.5, and 0.7, respectively), inflammatory bowel disease (0.01, 0.05, and 0.1, respectively), and major adverse cardiac events (0.3, 0.4, and 0.6, respectively). No cases of tuberculosis reactivation were reported. The incidence of treatment-emergent anti-drug antibodies was low with secukinumab across all studies, with no discernible loss of efficacy, unexpected alterations in pharmacokinetics, or association with immunogenicity-related AEs. CONCLUSIONS: Secukinumab demonstrated a favorable safety profile over long-term treatment in patients with PsO, PsA, and AS. This comprehensive assessment demonstrated that the safety profile of secukinumab was consistent with previous reports in patients with PsO, PsA, and AS, supporting its long-term use in these chronic conditions.

Safety and efficacy of infliximab in the treatment of refractory uveoretinitis in Behçet's disease: a large-scale, long-term postmarketing surveillance in Japan.

BACKGROUND: Infliximab, an anti-tumor necrosis factor-alpha antibody, has been reported to have excellent efficacy for refractory uveoretinitis in Behçet's disease (RUBD), and was approved for this indication in Japan. However, the long-term safety profile and efficacy in real-world clinical settings in patients with RUBD have not been fully clarified. The BRIGHT study, a prospective, large-scale, long-term postmarketing surveillance (PMS) study, was conducted to investigate the long-term safety and efficacy of infliximab in Japanese patients with RUBD. METHODS: All patients with RUBD who started infliximab treatment between January 2007 and January 2010 were enrolled. Safety was evaluated every 6 months for up to 24 months after initiation of therapy in 656 patients, and efficacy was evaluated in 650 patients. Patient characteristics were compared using the chi-square or Fisher's exact test. The frequency of ocular attacks before and after infliximab treatment was compared using the Wilcoxon signed-rank test. Independent associated factors for safety or efficacy were identified using multiple logistic regression analysis. A two-sided p value <0.05 was considered significant. RESULTS: Among the 656 patients evaluated for safety, 555 (84.6%) completed the 24-month study period. The incidence of adverse drug reactions (ADRs) and serious ADRs were 32.32% and 6.10%, respectively, and the safety profile was comparable to that of Japanese PMS of infliximab for other diseases. The most common ADRs and serious ADRs were infections (11.89% and 3.66%). Tuberculosis was reported in two patients, and Pneumocystis jirovecii in one. Identified independent associated factors for infections were comorbid respiratory disease, history of allergic disease, and concomitant use of glucocorticoids. Although infusion reactions were observed in 11.13% of patients, most were non-serious. The response rate at 24 months by physician global assessment was 80.7%. Median frequency of ocular attacks per 6 months significantly decreased compared with that before infliximab treatment (2.0 to 0.0), and corrected visual acuity was maintained during the study. CONCLUSIONS: Infliximab treatment had good tolerability and efficacy in Japanese patients with RUBD in this large-scale, long-term PMS. Infliximab treatment seemed to be a good treatment option for RUBD in real-world clinical settings. TRIAL REGISTRATION: UMIN Clinical Trials Registry, UMIN000027733 . Retrospectively registered on 6 June 2017.

The Role of European Healthcare Databases for Post-Marketing Drug Effectiveness, Safety and Value Evaluation: Where Does Italy Stand?

Enormous progress has been made globally in the use of evidence derived from patients' clinical information as they access their routine medical care. The value of real-world data lies in their complementary nature compared with data from randomised controlled trials: less detailed information on drug efficacy but longer observational periods and larger, more heterogeneous study populations reflecting clinical practice because individuals are included who would not usually be recruited in trials. Real-world data can be collected in various types of electronic sources, such as electronic health records, claims databases and drug or disease registries. These data sources vary in nature from country to country, according to national healthcare system structures and national policies. In Italy, a growing number of healthcare databases have been used to evaluate post-marketing drug utilisation and safety in the last two decades. The aim of this narrative review is to describe the available Italian sources of real-world data and their contribution to generating post-marketing evidence on drug use and safety. We also discuss the strengths and limitations of the most commonly used Italian healthcare databases in addressing various research questions concerning drug utilisation, comparative effectiveness and safety studies, as well as health technology assessment and other areas.

Safety and efficacy of Rapamune® (Sirolimus) in kidney transplant recipients: results of a prospective post-marketing surveillance study in Korea.

BACKGROUND: Few post-marketing surveillance studies have examined the safety and efficacy of Rapamune® (Sirolimus) in Asian countries. This study aimed to better understand safety and efficacy of Rapamune for kidney transplant recipients in the routine clinical practice setting in Korea. METHODS: This was an open-label, non-comparative, observational, prospective, multi-center, post-marketing surveillance study conducted at 15 Korean transplant centers between 31 August 2009 and 24 September 2015. The subjects were administered Rapamune as part of routine practice. The safety was monitored based on reporting of adverse events (AEs). Efficacy endpoints included acute rejection, graft function, graft survival, and patient survival. RESULTS: Rapamune was most commonly used for late conversion therapy after post-transplant 1 year and was substituted for anti-metabolites (63.6%) or calcineurin inhibitors (28.7%). The median treatment duration of Rapamune was 182 days. Among 209 subjects enrolled, AEs and adverse drug reactions (ADRs) were reported in 54.07% and 43.06% of subjects, respectively, in the safety analysis set. Most of the AEs were expected (96.21%), mild (75.83%), did not result in any action taken with regard to the study drug (72.99%), and resolved by the end of the study (75.36%). The most frequently reported AEs/ADRs were pharyngitis and diarrhea. Most of the serious AEs/ADRs occurred in one or two subjects. Unexpected ADRs of renal artery occlusion and cholangitis were reported by one subject each. The incidence of biopsy-proven acute rejection was 2.87%. At the end of the study, 99.51% of the subjects and their grafts had survived. The mean eGFR was 64.72 ± 19.56 mL/min. CONCLUSIONS: Rapamune had an acceptable safety profile in prevention of kidney allograft rejection in Korea.

The POST trial: initial post-market experience of the Penumbra system: revascularization of large vessel occlusion in acute ischemic stroke in the United States and Europe.

BACKGROUND AND PURPOSE: The purpose of this study was to assess the initial post-market experience of the device and how it is compared with the Penumbra Pivotal trial used to support the 510k application. METHODS: A retrospective case review of 157 consecutive patients treated with the Penumbra system at seven international centers was performed. Primary endpoints were revascularization of the target vessel (TIMI score of 2 or 3), good functional outcome as defined by a modified Rankin scale (mRS) score of ≤2 and incidence of procedural serious adverse events. Results were compared with those of the Penumbra pivotal trial. RESULTS: A total of 157 vessels were treated. Mean baseline values at enrollment were: age 65 years, NIHSS score 16. After use of the Penumbra system, 87% of the treated vessels were revascularized to TIMI 2 (54%) or 3 (33%) as compared with 82% reported in the Pivotal trial. Nine procedural serious adverse events were reported in 157 patients (5.7%). All-cause mortality was 20% (32/157), and 41% had a mRS of ≤2 at 90-day follow-up as compared with only 25% in the Pivotal trial. Patients who were successfully revascularized by the Penumbra system had significantly better outcomes than those who were not. CONCLUSION: Initial post-market experience of the Penumbra system revealed that the revascularization rate and safety profile of the device are comparable to those reported in the Pivotal trial. However, the proportion of patients who had good functional outcome was higher than expected.

North American Solitaire Stent Retriever Acute Stroke registry: post-marketing revascularization and clinical outcome results.

BACKGROUND: Limited post-marketing data exist on the use of the Solitaire FR device in clinical practice. The North American Solitaire Stent Retriever Acute Stroke (NASA) registry aimed to assess the real world performance of the Solitaire FR device in contrast with the results from the SWIFT (Solitaire with the Intention for Thrombectomy) and TREVO 2 (Trevo versus Merci retrievers for thrombectomy revascularization of large vessel occlusions in acute ischemic stroke) trials. METHODS: The investigator initiated NASA registry recruited North American sites to submit retrospective angiographic and clinical outcome data on consecutive acute ischemic stroke (AIS) patients treated with the Solitaire FR between March 2012 and February 2013. The primary outcome was a Thrombolysis in Myocardial Ischemia (TIMI) score of ≥2 or a Treatment in Cerebral Infarction (TICI) score of ≥2a. Secondary outcomes were 90 day modified Rankin Scale (mRS) score, mortality, and symptomatic intracranial hemorrhage. RESULTS: 354 patients underwent treatment for AIS using the Solitaire FR device in 24 centers. Mean time from onset to groin puncture was 363.4±239 min, mean fluoroscopy time was 32.9±25.7 min, and mean procedure time was 100.9±57.8 min. Recanalization outcome: TIMI ≥2 rate of 83.3% (315/354) and TICI ≥2a rate of 87.5% (310/354) compared with the operator reported TIMI ≥2 rate of 83% in SWIFT and TICI ≥2a rate of 85% in TREVO 2. Clinical outcome: 42% (132/315) of NASA patients demonstrated a 90 day mRS ≤2 compared with 37% (SWIFT) and 40% (TREVO 2). 90 day mortality was 30.2% (95/315) versus 17.2% (SWIFT) and 29% (TREVO 2). CONCLUSIONS: The NASA registry demonstrated that the Solitaire FR device performance in clinical practice is comparable with the SWIFT and TREVO 2 trial results.

Review of Transporter-Related Postmarketing Requirement or Postmarketing Commitment Studies.

The objectives of this report are to summarize the content and status of transporter-related postmarketing requirement (PMR)/postmarketing commitment (PMC) studies in new drug applications (NDAs) approved by the U.S. Food and Drug Administration (FDA) and to discuss the reasons for requesting such studies and the impact of PMR/PMC study results on labeling to guide the optimal use of the drugs. Multiple data sources were searched to collect information on transporter-related PMR/PMC studies between January 1999 and May 2015. A total of 40 transporter-related PMR/PMC study requests were issued for 35 NDAs. Among these PMR/PMC studies, 27 requested studies related to P-glycoprotein. As of May 31, 2015, 34 transporter-related PMR/PMC studies (85%) are considered "fulfilled" (per the FDA's PMR/PMC website), and 22 (65%) resulted in labeling updates. The majority of the PMR/PMC studies are for drugs in the therapeutic areas of anti-infectives, oncology, and neurology. The results from PMR/PMC studies are important for dosing optimization and are often included in the updated labeling. Because a significant lag time is anticipated between drug approval and PMR/PMC fulfillment, NDA applicants are encouraged to include transporter-related assessments in clinical drug development programs for drug products.

A large, multicentre, observational, post-marketing surveillance study of the 2:1 formulation of follitropin alfa and lutropin alfa in routine clinical practice for assisted reproductive technology.

BACKGROUND: Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) both have a role to play in follicular development during the natural menstrual cycle. LH supplementation during controlled ovarian stimulation (COS) for assisted reproductive technology (ART) is used for patients with hypogonadotropic hypogonadism. However, the use of exogenous LH in COS in normogonadotropic women undergoing ART is the subject of debate. The aim of this study was to investigate characteristics of infertile women who received the 2:1 formulation of follitropin alfa and lutropin alfa (indicated for stimulation of follicular development in women with severe LH and FSH deficiency) in German clinical practice. METHODS: A 3-year, multicentre, open-label, observational/non-interventional, post-marketing surveillance study of women (21-45 years) undergoing ART. Primary endpoint: reason for prescribing the 2:1 formulation of follitropin alfa and lutropin alfa. Secondary variables included: COS duration/dose; oocytes retrieved; fertilization; clinical pregnancy; ovarian hyperstimulation syndrome (OHSS). RESULTS: In total, 2220 cycles were assessed; at least one reason for prescribing the 2:1 formulation was given in 1834/2220 (82.6%) cycles. Most common reasons were: poor ovarian response (POR) (39.4%), low baseline LH (17.8%), and age (13.8%). COS: mean dose of the 2:1 formulation on first day, 183.1/91.5 IU; mean duration, 10.8 days. In 2173/2220 (97.9%) cycles, human chorionic gonadotrophin was administered. Oocyte pick-up (OPU) was attempted in 2108/2220 (95.0%) cycles; mean (standard deviation) 8.0 (5.4) oocytes retrieved/OPU cycle. Fertilization (≥1 oocyte fertilized) rates: in vitro fertilization (IVF), 391/439 (89.1%) cycles; intracytoplasmic sperm injection (ICSI)/IVF + ICSI, 1524/1613 (94.5%) cycles. Clinical pregnancy rate: all cycles, 25.9%; embryo transfer cycles, 31.3%. OHSS: hospitalization for OHSS, 8 (0.36%) cycles, Grade 2, 60 (2.7%), and Grade 3, 1 (0.05%). CONCLUSIONS: In German routine clinical practice, the most common reasons for using the 2:1 formulation of follitropin alfa and lutropin alfa for women undergoing ART were POR, low baseline LH, and age. Severe OHSS incidence was low and similar to that reported previously.

Juvenile idiopathic arthritis and malignancy.

Biologic agents represent a major advance in the treatment of JIA. In 2008 a US Food and Drug Administration (FDA) warning raised the hypothesis that anti-TNF therapies may be associated with anincreased incidence of malignancies in children. More recent data seem to suggest that JIA itself, as in the case of RA, is associated with an increased risk of malignancy and that this risk is not further increased with anti-TNF treatment. However, only long-term prospective data on a very large number of patients will provide a definite answer. This article summarizes the current evidence in order to help health professionals properly advise patients and their families about the possible risk of malignancies in JIA treated with biologic agents.

Is there a need for a universal benefit-risk assessment framework for medicines? Regulatory and industry perspectives.

PURPOSE: To explore the current status and need for a universal benefit-risk framework for medicines in regulatory agencies and pharmaceutical companies. METHODS: A questionnaire was developed and sent to 14 mature regulatory agencies and 24 major companies. The data were analysed using descriptive statistics, for a minority of questions preceded by manual grouping of the responses. RESULTS: Overall response rate was 82%, and study participants included key decision makers from agencies and companies. None used a fully quantitative system, most companies preferring a qualitative method. The major reasons for this group not using semi-quantitative or quantitative systems were lack of a universal and scientifically validated framework. The main advantages of a benefit-risk framework were that it provided a systematic standardised approach to decision-making and that it acted as a tool to enhance quality of communication. It was also reported that a framework should be of value to both agencies and companies throughout the life cycle of a product. They believed that it is possible to develop an overarching benefit-risk framework that should involve relevant stakeholders in the development, validation and application of a universal framework. The entire cohort indicated common barriers to implementing a framework were resource limitations, a lack of knowledge and a scientifically validated and acceptable framework. CONCLUSIONS: Stakeholders prefer a semi-quantitative, overarching framework that incorporates a toolbox of different methodologies. A coordinating committee of relevant stakeholders should be formed to guide its development and implementation. Through engaging the stakeholders, these outcomes confirm sentiments and need for developing a universal benefit-risk assessment framework.

Natalizumab: bench to bedside and beyond.

Natalizumab has been available as a multiple sclerosis treatment for more than 5 years in Europe and the United States. Natalizumab was granted approval by the US Food and Drug Administration in 2004, only 12 years after its molecular target was cloned. Shortly after initial approval, natalizumab use was suspended pending a safety review when several natalizumab recipients were diagnosed as having progressive multifocal leukoencephalopathy. After the safety review, natalizumab was reintroduced to the market in 2006. Since then, more than 92,000 patients have been treated with the drug. Risk stratification algorithms and progressive multifocal leukoencephalopathy management strategies have been developed, which facilitate more personalized decision making and safer natalizumab use. This review article summarizes the evolution of natalizumab from target molecule discovery through regulatory approval, voluntary suspension, reapproval, and clinical use. The natalizumab story highlights both the opportunities and risks inherent in a novel biological therapy for a progressive neurologic disease.