Postmarketing Surveillance Data Research Articles

Treatment of acute bleeding in acquired haemophilia A with recombinant activated factor VII: analysis of 10-year Japanese postmarketing surveillance data.

Patients with acquired haemophilia A (AHA) have autoantibodies against factor VIII (FVIII), and may develop spontaneous bleeding that requires treatment with FVIII inhibitor bypassing agents such as recombinant activated FVII (rFVIIa, NovoSeven® ). However, data regarding the use of rFVIIa are limited. To investigate the use, efficacy and safety of rFVIIa for the treatment of AHA by analysis of 10-year multicentre Japanese postmarketing surveillance data. Treatment regimens, haemostatic efficacy and adverse events were recorded for rFVIIa therapy of AHA patients with bleeding episodes. Treatment was evaluated as markedly effective, effective, moderate or ineffective. Data were collected for 371 bleeding episodes in 132 patients. Bleeding improved after rFVIIa therapy in 92% of episodes (markedly effective in 41%, effective in 10%, moderate in 41%). The response rate was significantly better in patients who received an initial dose of ≥90 μg kg-1 than in those who received an initial dose of <90 μg kg-1 . The response rate was also significantly better when rFVIIa was administered earlier after the onset of bleeding. Twelve serious adverse events were recorded in six patients, including five serious thromboembolic events in three patients who were all elderly with significant comorbidities. This is the largest, single-country study of rFVIIa therapy in AHA patients reported to date. The Japanese surveillance data show comparable efficacy and safety to prior multinational studies. Doses of 90-120 μg kg-1 and prompt initiation of treatment may be important to achieve good bleeding control.

Concomitant use of psychotropics and donepezil in Japanese patients with dementia: Pooled postmarketing surveillance data analysis

Background/PurposePsychotropics are administered to control behavioral and psychological symptoms of dementia. In 2005, the Food and Drug Administration (FDA) issued alerts regarding their use as antipsychotics in elderly patients with dementia-related psychosis. Guidelines on psychotropic use were also recently established in Japan; however, few studies have reported on the actual usage of psychotropics among patients with dementia in clinical settings. The aim of this study was to estimate the frequency of psychotropic use in patients with Alzheimer's disease receiving donepezil. MethodsData from six prospective, postmarketing studies of donepezil in patients with Alzheimer's disease conducted between 1999 and 2011 were pooled for analysis. Patient and clinical characteristics at baseline were analyzed descriptively. The proportion of psychotropics used concomitantly with donepezil was calculated for all patients and for patients divided into types of psychotropics used, sex, age, and study time period. As for the study time period, studies were divided into two groups: the period before the FDA alert was issued (1994–2004) and the period after (2005–2011). ResultsA total of 14,726 patients were analyzed (67.0% women, aged 79.3 ± 7.2 years). The overall proportion of psychotropic use was 24.2%. The number of psychotropics used was one in 8.2% of patients, two in 8.1%, and ≥ 3 in 5.5%. The types of psychotropics used were as follows: typical antipsychotics, 7.8%; atypical antipsychotics, 4.4%; antidepressants, 5.7%; anxiolytics, 6.4%; and hypnotics, 11.0% (% does not sum up to 24.2% due to multiple use). With regards to the time periods, in studies conducted between 1999 and 2004 versus those between 2005 and 2011, the proportions were 31.7% and 21.3%, respectively. ConclusionPsychotropic use was seen in a quarter of patients with dementia receiving donepezil in Japan. Additionally, the overall proportion decreased after the alert issued by the FDA in 2005.

Medication Safety

Medication Safety

Estimation of minimal clinically important change of the Japanese version of EQ-5D in patients with chronic noncancer pain: a retrospective research using real-world data.

BackgroundQuality of life (QoL) is routinely assessed and evaluated in medical research. However, in Japan, there is a lack of solid cutoff criteria for evaluating QoL improvement in chronic noncancer pain management. The present study was conducted to identify the minimal clinically important change (MCIC) of the Japanese version of EuroQol-5D 3L(EQ-5D) utility score and numeric rating scale (NRS) with an emphasis on chronic noncancer pain.MethodsThe data source for this post hoc research was the post-marketing surveillance (PMS) data for a tramadol/acetaminophen combination tablet, which was previously conducted in real-world settings. The parameters extracted from the PMS data were sociodemographic characteristics, NRS, EQ-5D, and dichotomous physician’s global impression of treatment effectiveness (PGI). The optimal cutoff points of MCIC for EQ-5D utility and NRS scores were evaluated using receiver operating characteristics (ROC) analysis. An anchor-based approach using PGI was applied.ResultsData of 710 patients with chronic noncancer pain were extracted from the PMS database. The NRS score decreased by 2.7 (standard deviation, 2.3) points, whereas the EQ-5D score increased by 0.16 (0.20) points at 4 weeks from baseline. The changes from baseline in NRS and EQ-5D were significantly correlated (r = 0.53, p < 0.001). The estimated optimal cutoff points of MCIC for EQ-5D and NRS were 0.10 and −2.0 points, respectively. The area under the curve of ROC was > 0.80 in both analyses.ConclusionThese results demonstrated novel cutoff criteria for the Japanese version of EQ-5D, focusing on patients with chronic noncancer pain. The obtained criteria were fairly consistent and can be confidently utilized as an evaluation tool in medical research on chronic noncancer pain in Japan, with additional functionality and usability for QoL assessment in pain management practice.Trial registrationThe data source of this post hoc research was a PMS study with the identifier number UMIN000015901 at umin.ac.jp, UMIN clinical trial registry (UMIN-CTR).

Cost-Effectiveness of Implantable Pulmonary Artery Pressure Monitoring in Chronic Heart Failure

ObjectivesThis study aimed to evaluate the cost-effectiveness of the CardioMEMS (CardioMEMS Heart Failure System, St Jude Medical Inc, Atlanta, Georgia) device in patients with chronic heart failure. BackgroundThe CardioMEMS device, an implantable pulmonary artery pressure monitor, was shown to reduce hospitalizations for heart failure and improve quality of life in the CHAMPION (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients) trial. MethodsWe developed a Markov model to determine the hospitalization, survival, quality of life, cost, and incremental cost-effectiveness ratio of CardioMEMS implantation compared with usual care among a CHAMPION trial cohort of patients with heart failure. We obtained event rates and utilities from published trial data; we used costs from literature estimates and Medicare reimbursement data. We performed subgroup analyses of preserved and reduced ejection fraction and an exploratory analysis in a lower-risk cohort on the basis of the CHARM (Candesartan in Heart failure: Reduction in Mortality and Morbidity) trials. ResultsCardioMEMS reduced lifetime hospitalizations (2.18 vs. 3.12), increased quality-adjusted life-years (QALYs) (2.74 vs. 2.46), and increased costs ($176,648 vs. $156,569), thus yielding a cost of $71,462 per QALY gained and $48,054 per life-year gained. The cost per QALY gained was $82,301 in patients with reduced ejection fraction and $47,768 in those with preserved ejection fraction. In the lower-risk CHARM cohort, the device would need to reduce hospitalizations for heart failure by 41% to cost <$100,000 per QALY gained. The cost-effectiveness was most sensitive to the device’s durability. ConclusionsIn populations similar to that of the CHAMPION trial, the CardioMEMS device is cost-effective if the trial effectiveness is sustained over long periods. Post-marketing surveillance data on durability will further clarify its value.

Composite sequential Monte Carlo test for post-market vaccine safety surveillance.

Group sequential hypothesis testing is now widely used to analyze prospective data. If Monte Carlo simulation is used to construct the signaling threshold, the challenge is how to manage the type I error probability for each one of the multiple tests without losing control on the overall significance level. This paper introduces a valid method for a true management of the alpha spending at each one of a sequence of Monte Carlo tests. The method also enables the use of a sequential simulation strategy for each Monte Carlo test, which is useful for saving computational execution time. Thus, the proposed procedure allows for sequential Monte Carlo test in sequential analysis, and this is the reason that it is called 'composite sequential' test. An upper bound for the potential power losses from the proposed method is deduced. The composite sequential design is illustrated through an application for post-market vaccine safety surveillance data.

Abstract 19228: Cost-effectiveness of the CardioMems Implantable Pulmonary Artery Pressure Monitoring System in Patients With Chronic Heart Failure

Background: For management of heart failure, the value of the CardioMems device remains uncertain. We assessed the cost-effectiveness of the CardioMems device. Methods: We developed a Markov model to determine quality-adjusted life-years (QALYs), cost, and cost-effectiveness of patients with heart failure receiving CardioMems implantation compared to those with routine care. In the main case analysis, we modeled the intervention in the CHAMPION trial cohort, which included patients with NYHA Class III heart failure with a heart failure hospitalization within the past twelve months. We also performed subgroup analyses of patients with preserved ejection fraction or reduced ejection fraction, and a scenario analysis of a second cohort of patients from the CHARM trials with a previous heart failure hospitalization. We obtained event rates and utilities from published trial data; we used costs from literature estimates and Medicare payment data. The main case analysis was calibrated to the hospitalization and survival rates of the CHAMPION trial. Results: In the CHAMPION trial main case analysis, CardioMems reduced lifetime hospitalizations (2.37 versus 3.27), increased months of survival (67 versus 62), increased QALYs (2.66 versus 2.38) and increased costs ($171,132 versus $154,084), yielding a cost of $59,520 per QALY gained or $40,301 per life-year gained. The cost per QALY gained was $71,964 in patients with reduced ejection fraction compared to $34,899 in those with preserved ejection fraction. In less ill patients from the CHARM trials, which included patients with NYHA Class II heart failure, the device cost increased to $110,565 per QALY gained. If the device cost decreased from $17,500 in the main case analysis to $15,000, the intervention would cost less than $50,000 per QALY gained. The duration of effectiveness was initially assumed to be lifelong; if less than 29 months, CardioMems would cost more than $150,000 per QALY gained. Conclusion: The CardioMems device is cost-effective in populations similar to the CHAMPION trial, with a cost of less than $100,000 per QALY gained, if durability of device effectiveness is sustained. Post-marketing surveillance data on the device’s durability will further clarify its value.

Postmarketing Safety Profile of Subcutaneous Interferon Beta-1a Given 3 Times Weekly: A Retrospective Administrative Claims Analysis.

Health insurance administrative claims databases represent a valuable source of information regarding the safety profile of marketed products as used in actual clinical practice in a broader range of patients than that assessed in clinical trials. Interferon beta-1a administered subcutaneously 3 times weekly (IFN β-1a SC tiw), which was approved in 2002 by the FDA for the treatment of relapsing-remitting multiple sclerosis (MS), has over a decade of postmarketing experience. To date, however, its postmarketing safety profile has not been described using a real-world evidence source such as administrative claims data. To describe the safety profile of IFN β-1a SC tiw as presented in its U.S. prescribing information (PI) for patients with MS initiating IFN β-1a SC tiw therapy using data from U.S. health care administrative claims databases. This study featured an observational and retrospective "new start" cohort design using data from the Truven MarketScan Commercial and Medicare Supplemental health care administrative claims databases. Patients were eligible for inclusion if they were aged ≥ 18 years; had ≥ 1 diagnosis for MS recorded between January 1, 2006, and December 31, 2012; had ≥ 2 prescriptions for IFN β-1a SC tiw; and had ≥ 90 days of continuous eligibility pre-index date and ≥ 180 days of continuous eligibility post-index date. Patients with a prescription for IFN β-1a SC tiw without a MS diagnosis were excluded. Patients were followed from first prescription for IFN β-1a SC tiw (index date) until date of therapy switch or discontinuation, end of insurance eligibility, or end of observation period. Adverse events (AEs) examined were those listed in the Warnings and Precautions, Adverse Reactions, and Postmarketing Experience sections of the 2014 U.S. PI. Outcomes of interest were identified at the Medical Dictionary for Regulatory Activities (version 17.1) Preferred Term level and then coded to the corresponding ICD-9-CM criteria. Descriptive analyses of patient demographic, health status, health care utilization, and adherence status were performed, and incidence rates (IRs) per 100 person-years of labeled AEs with corresponding 95% CIs were calculated. The IR calculation was based on events that presented after therapy initiation and that were not present in the 90-day pre-index period. The top 6 AEs included influenza-like symptoms (IR = 15.65, 95% CI = 14.96-16.36); malaise (IR = 15.33, 95% CI = 14.65-16.04; fatigue (IR = 15.02, 95% CI = 14.35-15.72); abdominal pain (IR = 10.18, 95% CI = 9.67-10.70); chest pain (IR = 8.48, 95% CI = 8.03-8.95); and depression (IR = 7.75, 95% CI = 7.32-8.20). In contrast, the 6 lowest IRs were for maculo-papular rash (IR = 0.01, 95% CI = 0.00-0.04; injection-site necrosis (IR = 0.01, 95% CI = 0.00-0.03); erythema multiforme (IR = 0.01, 95% CI = 0.00-0.04); hypoesthesia (IR = 0.00, 95% CI = 0.00-0.02); Stevens-Johnson Syndrome (IR = 0.00, 95% CI = 0.00-0.02); and xerophthalmia (IR = 0.00, 95% CI = 0.00-0.02). Study results show strong convergence between the real-world safety profile of IFN β-1a SC tiw and its U.S. label. Our findings demonstrate the value of using real-world evidence obtained from administrative claims to complement clinical trial and postmarketing surveillance data in order to characterize the safety profile of established products, such as IFN β-1a SC tiw, in the postmarketing context.

Optimizing Postmarket Surveillance Reports

When designing a medical product, manufacturers must ensure the benefits outweigh the risks to the patient. Companies often have internal, confidential methods to gather postmarket surveillance data; however, not all of that important user information is reported directly to the company. ![Figure][

Gadobutrol for contrast-enhanced magnetic resonance imaging in elderly patients: review of the safety profile from clinical trial, post-marketing surveillance, and pharmacovigilance data

To assess the safety of gadobutrol administration in elderly patients (≥65 years) by comparing the incidence of adverse drug reactions (ADRs) following gadobutrol-enhanced magnetic resonance imaging (MRI) procedures in elderly patients with that in adults aged 18-64 years. Safety data on gadobutrol administration from clinical trials, post-marketing surveillance (PMS) studies, and pharmacovigilance reports were collected in three databases. In each dataset, absolute and relative frequencies of ADRs between age groups were analysed, along with odds ratios and 95% confidence intervals. Logistic regression was used to identify significant influencing factors on ADRs in the PMS and pharmacovigilance data. Rates of reported ADRs were lower in elderly patients versus adults aged <65 years due to a reduced incidence of non-serious ADRs; this was statistically significant for the clinical trials and pharmacovigilance populations, with a trend in the PMS database. Serious ADRs occurred infrequently in the clinical trials and PMS populations (too low for statistical comparison), and pharmacovigilance data demonstrated a low incidence (<0.005%) in both age groups. This evaluation involving three large databases demonstrated no greater incidence of ADRs following gadobutrol-enhanced MRI in elderly patients (≥65 years) compared with younger adults, with gadobutrol having a favourable safety profile in both age groups.

Ocriplasmin for the Treatment of Symptomatic Vitreomacular Adhesion/Traction

Ocriplasmin has recently been introduced as a new treatment option for patients with symptomatic vitreomacular adhesion/vitreomacular traction (VMA/VMT). Understanding its potential as well as its limitations is crucial as it becomes an additional tool in the management of these diseases. In this article the overall efficacy and safety of ocriplasmin are reviewed, focusing on the results from the phase III clinical trials as well as recently published case reports and postmarketing data analysis. Efficacy data from ocriplasmin use in a clinical setting support the subanalysis of the phase III clinical trial data. This analysis demonstrated that certain baseline ocular characteristics, namely focal VMA, and absence of epiretinal membrane, are predictive of VMA resolution. Safety findings show that the overall percentage of patients experiencing adverse events during the clinical trial program was low in ocriplasmin-treated patients. Postmarketing surveillance data corroborate findings from the phase III trials, and provide additional insights into the characterization of the safety profile of this new treatment option.

Ocriplasmin for the Treatment of Symptomatic Vitreomacular Adhesion/Traction

Ocriplasmin has recently been introduced as a new treatment option for patients with symptomatic vitreomacular adhesion/vitreomacular traction (VMA/VMT). Understanding its potential as well as its limitations is crucial as it becomes an additional tool in the management of these diseases. In this article the overall efficacy and safety of ocriplasmin are reviewed, focusing on the results from the phase III clinical trials as well as recently published case reports and postmarketing data analysis. Efficacy data from ocriplasmin use in a clinical setting support the subanalysis of the phase III clinical trial data. This analysis demonstrated that certain baseline ocular characteristics, namely focal VMA, and absence of epiretinal membrane, are predictive of VMA resolution. Safety findings show that the overall percentage of patients experiencing adverse events during the clinical trial program was low in ocriplasmin-treated patients. Postmarketing surveillance data corroborate findings from the phase III trials, and provide additional insights into the characterization of the safety profile of this new treatment option.

Ten-year experience of recombinant activated factor VII use in surgical patients with congenital haemophilia with inhibitors or acquired haemophilia in Japan.

Patients with congenital haemophilia with inhibitors or acquired haemophilia are at risk of bleeding complications during surgery. In these patients, replacement therapy for the missing coagulation factor is ineffective, and a bypassing agent such as recombinant activated factor VII (rFVIIa) is required to manage bleeding. To evaluate the safety and haemostatic efficacy of rFVIIa treatment in Japanese patients with congenital haemophilia with inhibitors to FVIII/FIX or acquired haemophilia undergoing surgery. Postmarketing surveillance data from May 2000 to March 2010 were analysed to assess the haemostatic efficacy of 38 procedures in 22 patients with congenital haemophilia A, 13 procedures in seven patients with congenital haemophilia B, and five procedures in five patients with acquired haemophilia. Postoperative bleeding control was judged to be effective (bleeding was stopped completely or reduced considerably) for 34/38 procedures (89%) in patients with congenital haemophilia A, 10/13 procedures (77%) in patients with congenital haemophilia B, and 4/5 procedures (80%) in patients with acquired haemophilia. Tranexamic acid was used concomitantly for 36/56 procedures (64%). Safety was analysed for 66 procedures in 37 patients. Adverse effects potentially related to rFVIIa treatment included mild superficial thrombophlebitis, mild decrease in platelet count, and mild elevation of the serum alanine transaminase level in one patient each. All adverse effects resolved without treatment. Administration of rFVIIa provided adequate haemostasis without serious adverse effects in the majority of cases. The efficacy and safety data in Japanese patients were similar to previously published data from other countries.

Adverse events following vaccination with an inactivated, Vero cell culture-derived Japanese encephalitis vaccine in the United States, 2009–2012

BackgroundIn March 2009, the U.S. Food and Drug Administration licensed an inactivated, Vero cell culture-derived Japanese encephalitis vaccine (JE-VC [Ixiaro]) for use in adults. The vaccine was licensed based on clinical trial safety data in 3558 JE-VC recipients. It is essential to monitor post-licensure surveillance data to evaluate the safety of JE-VC because rare adverse events may not be detected until the vaccine is administered to a larger population. MethodsWe reviewed adverse events reported to the U.S. Vaccine Adverse Event Reporting System (VAERS) for adults (≥17 years) who received JE-VC from May 2009 through April 2012. Adverse event reporting rates were calculated using 275,848 JE-VC doses distributed. ResultsOver the 3 year period, 42 adverse events following vaccination with JE-VC were reported to VAERS for an overall reporting rate of 15.2 adverse events per 100,000 doses distributed. Of the 42 total reports, 5 (12%) were classified as serious for a reporting rate of 1.8 per 100,000 doses distributed; there were no deaths. Hypersensitivity reactions (N=12) were the most commonly reported type of adverse event, with a rate of 4.4 per 100,000 doses distributed; no cases of anaphylaxis were reported. Three adverse events of the central nervous system were reported (one case of encephalitis and two seizures) for a rate of 1.1 per 100,000; all occurred after receipt of JE-VC with other vaccines. ConclusionsThese post-marketing surveillance data suggest a good safety profile for JE-VC consistent with findings from pre-licensure clinical trials. Post-licensure safety data should continue to be monitored for any evidence of rare serious or neurologic adverse events.

Analysis of 3 Year Post Marketing Surveillance of Eculizumab in Japan

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a disease characterized by chronic complement-mediated hemolysis, leading to life-threatening events, such as thromboembolism (TE) and chronic kidney disease (CKD), and devastated quality of life (QOL). The terminal complement inhibitor eculizumab (ECU) was approved in Japan in 2010 under the indication to suppress hemolysis in PNH. We comprehensively report as post marketing surveillance (PMS) on the efficacy and safety of ECU administered from June 2010 to March 2013 in Japanese patients with PNH. In spite of complete blocking hemolysis, the degree of improvement of anemia by ECU treatment varies patient by patient. Analyzing the data of PMS, we investigated if patient characteristics, such as LDH, bone marrow function and renal function, can affect anemia in PNH patients treated with ECU.Methods: The PMS data of 242 patients were used for demographics and safety assessment. Of 242, 144 patients with ECU treatment at least for 1 year were analyzed for efficacy evaluation. We used platelet (PLT) count as a marker of bone marrow function and divided it into three groups, <88 (Low), 88-155 (Mid) and ≧155 x109/L (High). We also utilized CKD stage calculated by estimated GFR (eGFR) which is widely accepted as a renal function classification, eGFR <60 (CKD stage 3-5), 60-90 (CKD stage 2) and ≧90 mL/min/1.73m2 (CKD stage 0/1), according to Japanese CKD guideline.Results: In Japan LDH>1000 IU/L is commonly considered as ECU applicable severe PNH patients, but this was not correlated with other markers related to PNH severity. 41.2% of patients who started ECU had eGFR <60 mL/min/1.73m2, CKD stage 3-5. The prevalence of CKD stage 3-5 in PNH population was much higher than that of the normal Japanese population, especially in PNH patients over 65 years old. ECU treatment dramatically and quickly reduced the serum level of LDH, and 18-month (median)-teatment with ECU increased hemoglobin level by 1.9 g/dL, reduced annual transfusion units by half, made 55.3% of transfusion-dependent patients transfusion-independent, improved one CKD stage in 29% of the patients with CKD stage 3-5 and made 14% returned to CKD stage 2. Side effects of all grades associated with ECU were reported in 36.8% of patients and severe ones were observed in 8.3%, which include 10 infectious events in 8 patients. 18-month-treatment with ECU increased hemoglobin (Hb) level by 1.2 g/dL in the Low-PLT, 1.5 g/dL (p<0.001) in the Mid-PLT and 2.9 g/dL (p<0.001) in the High-PLT group and reduced annual RBC transfusion (TF) unit 21.6→11.3 (p=0.002), 11.0→7.0 and 10.0→1.1 (p<0.001), respectively. ECU augmented Hb level by 2.4 g/dL (p<0.001) in CKD stage 0/1, 2.3 g/dL (p<0.001) in CKD stage 2 and 1.1 g/dL (p=0.022) in CKD stage 3-5 and decreased annual TF units 13.4→2.9 (p<0.001), 11.5→3.3 (p=0001) and 16.5→10.4 (p=0.036), respectively.Conclusion: ECU treatment for 18 months reduced hemolysis and improved anemia, renal function and QOL. It is concluded that ECU is safe and well tolerated.Anemia in PNH would be caused not only by hemolysis but also modified by bone marrow as well as renal function. DisclosuresObara:Alexion Pharma: Research Funding. Ninomiya:Alexion Pharma: Honoraria, Research Funding. Chiba:Alexion Pharma: Research Funding. Usuki:Alexion Pharma: Speakers Bureau. Shichishima:Alexion Pharma: Honoraria, Research Funding. Nishimura:Alexion Pharma: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ohyashiki:Alexion Pharma: Honoraria, Research Funding. Nakao:Alexion Pharma: Honoraria, Research Funding. Ando:Alexion Pharma: Research Funding. Kawaguchi:Alexion Pharma: Honoraria, Research Funding. Nakakuma:Alexion Pharma: Honoraria. Hamada:Alexion Pharma: Employment. Shimono:Alexion Pharma: Employment. Kinoshita:Alexion Pharma: Honoraria. Ozawa:Alexion Pharma: Honoraria. Omine:Alexion Pharma: Honoraria. Kanakura:Alexion Pharma: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Did narcolepsy occur following administration of AS03-adjuvanted A(H1N1) pandemic vaccine in Ontario, Canada? A review of post-marketing safety surveillance data

A vaccine safety signal and association between new onset of narcolepsy and AS03-adjuvanted pandemic influenza A(H1N1) vaccine (Pandemrix, GlaxoSmithKline) in children and young adults has been reported in several European countries. In Ontario, Canada, AS03-adjuvanted pandemic A(H1N1) vaccine (Arepanrix, GlaxoSmithKline) was the primary vaccine administered in 2009/10, with 4.8 million doses distributed. We assessed post-marketing safety surveillance data by extracting adverse events following immunisation (AEFIs) associated with this vaccine from the integrated Public Health Information System. Reports were screened for key terms related to narcolepsy and further limited to children and young adults four to 29 years of age. Of 1,604 AEFIs reported in Ontario, 53 reports met the search criteria. Individual assessment by a nurse consultant for additional context suggestive of narcolepsy yielded five reports for secondary medical review. None of the five reports proved consistent with a possible narcolepsy diagnosis based on the available information. We present the first post-marketing assessment from Canada of narcolepsy reports following receipt of Arepanix. Continued investigation of differences between Arepanrix and Pandemrix and subsequent risk of narcolepsy is indicated. In light of the limitations of passive surveillance to detect a signal in this instance, validation using other data sources is prudent.

Post-marketing surveillance of live-attenuated Japanese encephalitis vaccine safety in China

Japanese encephalitis (JE) is the most severe form of viral encephalitis in Asia and no specific treatment is available. Vaccination provides an effective intervention to prevent JE. In this paper, surveillance data for adverse events following immunization (AEFI) related to SA-14-14-2 live-attenuated Japanese encephalitis vaccine (Chengdu Institute of Biological Products) was presented. This information has been routinely generated by the Chinese national surveillance system for the period 2009–2012. There were 6024 AEFI cases (estimated reported rate 96.55 per million doses). Most common symptoms of adverse events were fever, redness, induration and skin rash. There were 70 serious AEFI cases (1.12 per million doses), including 9 cases of meningoencephalitis and 4 cases of death. The post-marketing surveillance data add the evidence that the Chengdu institute live attenutated vaccine has a reasonable safety profile. The relationship between encephalitis and SA-14-14-2 vaccination should be further studied.

Statistical Methods for Active Pharmacovigilance, With Applications to Diabetes Drugs

Pharmacovigilance aims to identify adverse drug reactions using postmarket surveillance data under real-world conditions of use. Unlike passive pharmacovigilance, which is based on largely voluntary (and hence incomplete) spontaneous reports of adverse drug reactions with limited information on patient characteristics, active pharmacovigilance is based on electronic health records containing detailed information about patient populations, thereby allowing consideration of modifying factors such as polypharmacy and comorbidity, as well as sociodemographic characteristics. With the present shift toward active pharmacovigilance, statistical methods capable of addressing the complexities of such data are needed. We describe four such methods here, and demonstrate their application in the analysis of a large retrospective cohort of diabetics taking anti-hyperglycemic medications that may increase the risk of adverse cardiovascular events.

Post-marketing surveillance data of thrombomodulin alfa: sub-analysis in patients with sepsis-induced disseminated intravascular coagulation.

BackgroundThrombomodulin alfa (TM-α, recombinant thrombomodulin) significantly improved disseminated intravascular coagulation (DIC) when compared with heparin therapy in a phase III study. Post-marketing surveillance of TM-α was performed to evaluate the effects and safety in patients with sepsis-induced DIC.MethodsFrom May 2008 to April 2010, a total of 1,787 patients with sepsis-induced DIC treated with TM-α were registered. DIC was diagnosed based on the Japanese Association for Acute Medicine (JAAM) criteria. The DIC resolution and survival rates on day 28 after the last TM-α administration, and changes in DIC, systemic inflammatory response syndrome (SIRS), and sequential organ failure assessment (SOFA) scores and coagulation and inflammation markers were evaluated.ResultsThe most frequent underlying disease was infectious focus-unknown sepsis (29.8%). The mean ± SD values of age, dose, and the duration of TM-α administration were 64.7 ± 20.3 years, 297.3 ± 111.4 U/kg/day, and 5.6 ± 3.4 days, respectively. A total of 1,320 subjects (73.9%) received combined administration with other anticoagulants. Both coagulation and inflammation markers, such as fibrin/fibrinogen degradation products, prothrombin time ratio, thrombin-antithrombin complex, and C-reactive protein, as well as JAAM DIC, SIRS, and SOFA scores, significantly and simultaneously decreased after TM-α administration (p < 0.001). DIC resolution and 28-day survival rates were 44.4% and 66.0%, respectively. The 28-day survival rate decreased significantly according to the duration of DIC before TM-α administration (p < 0.001). Total adverse drug reactions (ADRs), bleeding ADRs, and serious bleeding adverse events occurred in 126 (7.1%), 98 (5.5%), and 121 (6.8%) subjects, respectively. On day 28, after the last TM-α administration available for an antibody test, only one patient was positive for anti-TM-α antibodies (0.11%).ConclusionOur results suggest that TM-α is most effective for treating patients with sepsis-induced DIC when administered within the first 3 days after diagnosis.

Metal Ion Levels After Metal-on-Metal Total Hip Arthroplasty

The U.S. Food and Drug Administration has requested post-market surveillance data, including data on metal ion levels, regarding metal-on-metal total hip arthroplasty. We performed a prospective, randomized study of metal ion levels in erythrocytes, serum, and whole blood at five years after 28 and 36-mm metal-on-metal and 28-mm metal-on-polyethylene total hip arthroplasty. One hundred and five enrolled patients were randomized equally to the three bearing surface options and were blinded with regard to their treatment group. Metal ion measurements and clinical evaluations were performed at regular intervals. Cobalt and chromium ion levels in all blood sample types at the five-year time point were significantly lower in the metal-on-polyethylene group than in each of the two metal-on-metal groups (p < 0.001) with the exception of chromium in erythrocytes (p = 0.194). Cobalt in serum (p = 0.029) and erythrocytes (p = 0.002) showed significant increases from two to five years in the 36-mm metal-on-metal group; similar increases were not seen in the 28-mm metal-on-metal group. At five years, five patients in the 36-mm metal-on-metal group and none in the 28-mm metal-on-metal group had cobalt or chromium levels of >7 ppb. Correlations among levels in serum, erythrocyte, and whole blood were stronger for cobalt than for chromium. One patient in the 36-mm metal-on-metal group underwent revision because of an adverse local tissue reaction. The 36-mm metal-on-metal bearing underperformed the 28-mm metal-on-metal bearing with respect to metal ion levels. The authors are closely following all patients treated with metal-on-metal total hip arthroplasty.