Clinical Safety Assessment Research Articles

A next-generation, serum-free, highly purified Vero cell rabies vaccine is safe and as immunogenic as the reference vaccine Verorab® when administered according to a post-exposure regimen in healthy children and adults in China

BackgroundAs an evolution of its currently licensed rabies vaccine Verorab®, Sanofi Pasteur has developed a next-generation, serum-free, highly purified Vero rabies vaccine (PVRV-NG). Through this Phase III clinical trial, we aimed to demonstrate the non-inferiority of PVRV-NG over Verorab when administered according to a post-exposure regimen and to assess its clinical safety. MethodsA total of 816 healthy subjects aged ≥10 years were randomized according to a 2:1 ratio to receive PVRV-NG or Verorab. Half of the subjects were aged 10–17 years, the other half were aged ≥18 years. All subjects were to receive 5 injections on days 0, 3, 7, 14 and 28. Three blood samples were taken for rabies virus neutralizing antibodies (RVNA) assessment, at baseline, on day 14 and day 42. Solicited adverse reactions (between injections 1, 2 and 3, and within 7 days post-injections 4 and 5) and adverse events (up to 28 days after the last injection) were collected for clinical safety assessment; serious adverse events were reported up to 6-months after the last injection. ResultsThe proportion of subjects with an RVNA titer ≥0.5IU/mL after the third injection of PVRV-NG was non-inferior to the proportion of those who received Verorab. PVRV-NG was shown to be as immunogenic as Verorab in each age range in the per-protocol and full analysis sets. PVRV-NG induced a strong immune response in both age ranges, with high RVNA levels and increased geometric mean titers compared to baseline after each measured time point. PVRV-NG had a satisfactory safety profile after each injection, similar to Verorab with regards to the nature, frequency, duration and severity of adverse events. Two serious adverse events were reported, none was related to vaccination. ConclusionsThis trial demonstrated the immunogenic non-inferiority of PVRV-NG over Verorab and showed that both vaccines have similar safety profiles. This trial is registered at ClinicalTrials.gov (NCT01339312). This manuscript is the first full report of the study. An abstract of the study results was previously presented at the Rabies in the Americas (RITA) conference in October 2012 in São Paulo, Brazil. FundingSanofi Pasteur.

Safety, Adherence and Acceptability of Intermittent Tenofovir/Emtricitabine as HIV Pre-Exposure Prophylaxis (PrEP) among HIV-Uninfected Ugandan Volunteers Living in HIV-Serodiscordant Relationships: A Randomized, Clinical Trial

BackgroundEfficacy of oral pre-exposure prophylaxis (PrEP) in prevention of HIV acquisition has been evaluated using a daily regimen. However, adherence to long term daily medication is rarely perfect. Intermittent regimen may be a feasible alternative. Preclinical studies have demonstrated effectiveness of intermittent PrEP in SHIV prevention among animals. However, little is known about intermittent PrEP regimens.DesignSeventy two HIV-uninfected volunteers in HIV serodiscordant couple relationships in Uganda were randomly assigned to receive daily oral Tenofovir/Emtricitabine (TDF/FTC-Truvada) or placebo, or intermittent (Monday, Friday and within 2 hours after sex, not to exceed one dose per day) oral TDF/FTC or placebo in a 2:1:2:1 ratio. Volunteers and study staff were blinded to drug assignment, but not to regimen assignment.MethodsVolunteers were followed for 4 months after randomization, with monthly clinical and laboratory safety assessments and comprehensive HIV risk reduction services. Adherence was monitored using medication event monitoring system (MEMS) and self-report. Sexual activity data were collected via daily short text message (SMS) and self-report. HIV-specific immune responses were assessed by IFN-γ ELISPOT.ResultsBoth daily and intermittent oral TDF/FTC regimens were well tolerated. Median MEMS adherence rates were 98% (IQR: 93-100) for daily PrEP regimen, 91% (IQR: 73-97) for fixed intermittent dosing and 45% (IQR: 20-63) for post-coital dosing. SMS response rate was 74%, but increased to 80% after excluding server outages; results may have been affected by the novelty of this measure. The majority of volunteers expressed willingness with no particular preference for either regimen.ConclusionsBoth daily and intermittent oral PrEP dosing regimens were safe. Adherence was high for daily and fixed intermittent dosing; post-coital dosing was associated with poor adherence. Fixed intermittent PrEP regimens may be feasible especially if a minimum effective drug concentration correlating with HIV prevention can be achieved with this dosing.Registration Clinicaltrials.gov number NCT00931346

Confirmation of in vitro and clinical safety assessment of behentrimonium chloride-containing leave-on body lotions using post-marketing adverse event data

Behentrimonium chloride (BTC) is a straight-chain alkyltrimonium chloride compound commonly used as an antistatic, hair conditioning, emulsifier, or preservative agent in personal care products. Although the European Union recently restricted the use of alkyltrimonium chlorides and bromides as preservatives to ⩽0.1%, these compounds have been safely used for many years at ⩽5% in hundreds of cosmetic products for other uses than as a preservative. In vitro, clinical, and controlled consumer usage tests in barrier-impaired individuals were conducted to determine if whole body, leave-on skin care products containing 1–5% BTC cause dermal irritation or any other skin reaction with use. BTC-containing formulations were predicted to be non-irritants by the EpiDerm® skin irritation test and the bovine corneal opacity and permeability (BCOP)/chorioallantoic membrane vascular assay (CAMVA) ocular irritation test battery. No evidence of allergic contact dermatitis or cumulative dermal irritation was noted under the exaggerated conditions of human occlusive patch tests. No clinically assessed or self-reported adverse reactions were noted in adults or children with atopic, eczematous, and/or xerotic skin during two-week and four-week monitored home usage studies. These results were confirmed by post-marketing data for five body lotions, which showed only 0.69 undesirable effects (mostly skin irritation) reported per million shipped consumer units during 2006–2011; a value consistent with a non-irritating body lotion. No serious undesirable effects were reported during in-market use of the products. Therefore, if formulated in appropriate conditions at 1–5%, BTC will not cause dermal irritation or delayed contact sensitization when used in a whole-body, leave-on product.

Platelet aggregation inhibition by Eptifibatide versus high dose Tirofiban during primary percutaneous interventions

Abstract Background Platelet aggregation occurs as a central role in acute coronary syndrome (ACS), and glycoprotein GP IIb/IIIa inhibitors may enhance the benefits expected from early recanalisation. Aim To compare the degree of platelet aggregation inhibition achieved by Eptifibatide versus high dose Tirofiban, and its clinical effects regarding myocardial reperfusion parameters: myocardial blush grade (MBG) and ST-segment resolution (STR) >70%, and regarding peri procedural complications, bleeding and major adverse cardiac events (MACE). Methods Between the period of June 2010–January 2012, 46 patients with acute myocardial infarction whose symptom onset is within 12 h of presentation and ECG showing ST-segment elevation 1 mm in two contiguous limb leads or 2 mm in two contiguous precordial leads or acute left bundle branch block were included. Exclusion criteria were active bleeding, thrombocytopenia, bleeding diathesis, anticoagulation or thrombolitics, recent major surgery or stroke, cardiogenic shock, and pregnancy. Patients were randomized alternatively (1:1) into two groups before primary percutaneous cardiac intervention (PCI) to receive the specific glycoprotin IIb/IIIa inhibitor as follows: (I) Tirofiban group: intravenous high bolus dose of 25 mcg/kg over 3 min followed by maintenance infusion of 0.15 mcg/kg/min. (II) Eptifibatide group: intravenous two boluses 10 min apart (each one is 180 mcg/kg) followed by maintenance of 2 mcg/kg/min. Platelet aggregation inhibition was measured by light transmission aggregometer, angiographic assessment was done before and after final interventions for TIMI flow and myocardial blush grade before and after the procedure. Electrocardiographic assessment standard 12-lead ECG on admission, immediately after PCI. Resolution of ST segment elevation was expressed as a percentage of the initial ST segment elevation. Resolution of ⩾70% was defined as complete resolution. Clinical safety assessment was done in terms of the incidence of: bleeding complications and major adverse cardiac events (MACE): death, non-fatal myocardial infarction (MI), and target vessel revascularization (TVR). Results The total patients in our study included 46 patients, 40 males (87%) and six females (13%) with a mean age of 55 ± 10, Tirofiban group: included 23 patients, 19 males (82.5%) and four females (17.4%) with a mean age of 57 ± 9.65. Eptifibatide group: included 23 patients, 21 males (87%) and two females (8.7%) with a mean age of 53.48 ± 8.6. Platelet aggregation inhibition during PCI was significantly correlated with STR (p 0.013, r 0.71). The cut-off point for platelet aggregation inhibition as a predictor of STR >70% was 89.5% (sensitivity 92.3%, specificity 69.2%, PPV 75% and NPV 10%, AUC 0.87). Platelet aggregation inhibition during PCI was positively correlated with MBG (p 0.045, r 0.453). The cut-off point for platelet aggregation inhibition as a predictor of MBG 2–3 was 87.5% (sensitivity 73.6%, specificity 66.7%, PPV 93.9% and NPV 76.9%, AUC 0.81). Platelet aggregation inhibition 60 min after bolus was (93.57 ± 2.07% versus 87.62 ± 3.2%, p 70% (56.22% versus 39.13%, p 0.005) in Eptifibatide versus Tirofiban group, respectively. There was no significant statistical difference regarding thrombocytopenia (46.73 ± 41.48 versus 39.04 ± 34.41, p 0.37), minor bleeding (17.4% versus 21.7%, p 0.5), major bleeding (0% versus 4.3%, p 0.5), post procedural infarction (0% versus 17.4%, p 0.12), TVR (0% versus 8.7%, p 0.24), MACE and 30 days mortality (4.3% versus 13%, p 0.34) in Eptifibatide versus Tirofiban group, respectively. Conclusions • Platelet aggregation inhibition during PCI was significantly correlated with STR and MBG. Platelet aggregation inhibition cut-off point as a predictor of STR >70% was 89.5%, and as a predictor of MBG 2–3 was 87.5%. • Eptifibatide achieves better platelet aggregation inhibition 60 min after bolus and 6 h after PCI than high dose Tirofiban. • Eptifibatide is associated with better myocardial perfusion as indicated by post procedural mean MBG and STR >70% than high dose Tirofiban. • There was no significant differences between Eptifibatide and high dose Tirofiban regarding thrombocytopenia, major or minor bleeding, MACE and 30 days mortality.

SAT0105 Summacta: A Randomized, Double-Blind, Parallel Group Study of the Safety and Efficacy Of Tocilizumab SC Versus Tocilizumab IV, in Combination with Traditional Dmards in Patients With Moderate to Severe Ra

BackgroundThe efficacy and safety profile of intravenous (IV) tocilizumab (TCZ) has been well established in patients (pts) with rheumatoid arthritis (RA). The aim of a subcutaneous (SC) TCZ dosing regimen...

Clinical assessment of efficacy and safety of a night cream containing vitamin C in facial photoaging

Clinical assessment of efficacy and safety of a night cream containing vitamin C in facial photoaging

Clinical Assessment of Serious Adverse Events in Children Receiving 2009 H1N1 Vaccination

Monovalent 2009 H1N1 influenza vaccines were licensed and administered in the United States during the H1N1 influenza pandemic between 2009 and 2013. Vaccine Adverse Event Reporting System received reports of adverse events following immunization (AEFI) after H1N1 vaccination. Selected reports were referred to the Centers for Disease Control and Prevention's Clinical Immunization Safety Assessment network for additional review. We assessed causality using modified World Health Organization criteria. There were 3,928 reports of AEFI in children younger than age 18 years after 2009 H1N1 vaccination received by January 31, 2010. Of these, 214 (5.4%) were classified as serious nonfatal and 109 were referred to Clinical Immunization Safety Assessment for further evaluation. Ninety-nine (91%) had sufficient initial information to begin investigation and are described here. The mean age was 8 years (range, 6 months-17 years) and 38% were female. Median number of days between vaccination and symptom onset was 2 (range, -11 days to +41 days). Receipt of inactivated, live attenuated, or unknown type of 2009 H1N1 vaccines was reported by 68, 26 and 5 cases, respectively. Serious AEFI were categorized as neurologic events in 47 cases, as hypersensitivity in 15 cases and as respiratory events in 10 cases. At the time of evaluation, recovery was described as complete (61), partial (16), no improvement (1), or unknown (21). Causality assessment yielded the following likelihood of association with 2009 H1N1 vaccination: 8 definitely; 8 probably; 21 possibly; 43 unlikely; 17 unrelated; and 2 unclassifiable. Most AEFI in children evaluated were not causally related to vaccine and resolved without sequelae. Detailed clinical assessment of individual serious AEFI can provide reassurance of vaccine safety.

Macro- and microperfusion during application of a new compression system, designed for patients with leg ulcer and concomitant peripheral arterial occlusive disease

To investigate macro- and microperfusion during 14 days of treatment with a new 2-layer compression system (3M™ Coban™ 2 Lite), designed for patients with leg ulcer and concomitant peripheral arterial occlusive disease. A single-centre, open-label, prospective pilot study was performed with 15 subjects suffering from peripheral arterial occlusive disease with an ankle brachial pressure index (ABPI) of 0.5-0.8, who volunteered to have their 'study leg' bandaged with the new system. Coincident leg ulcer or chronic venous disease was not mandatory. All subjects received the new compression system, which stayed in place from 1 up to 4 days according to scheduled study visits. The system was reapplied by study personnel at each clinical visit (days 1, 2, 3, 4, 7, 10 and 14). The study participation stopped after 14 days. At each clinical visit safety assessments were performed: measurement of acral pulsation to capture macroperfusion; laser Doppler fluxmetry to capture microperfusion; clinical signs of pressure related skin damage, hypoxia-related pain and sub-bandage pressure measurement. In addition, the leg volume was measured and a comfort questionnaire was completed. An average sub-bandage pressure in standing position of approximately 30 mmHg was measured at the B1 location immediately after bandage application. Laser Doppler fluxmetry demonstrated positive effects on microcirculation regarding vasomotion and respiratory reflux. No change of the cardiac signal appeared. For acrale pulsations a high intraindividual variability was found with no clear interference to the bandage application. No pressure-related skin damage or hypoxia-related pain was detected. After application of the new compression system in subjects with moderate PAOD, laser Doppler fluxmetry indicated significant improvements of the microcirculation. High variability and lack of correlation to clinical symptoms was found for the acral pulsation. The new compression system revealed a high grade of tolerability and a good safety profile.

The Clinical Area Safety Assessment, a Peer Review of Safety across an Acute Trust

Background Most hospitals have developed processes to manage risk in a reactive manner. Few, however, have instituted proactive systems for the identification of latent risk that has the potential to cause harm. Objective To develop a process for the identification of potential risks to safety across all clinical areas of a hospital. Methods Every clinical department in Cambridge University Hospitals Foundation Trust (CUHFT) underwent peer assessment to confirm that the Trust’s processes for safety were in place and identify possible threats to the safety of patients. This assessment consisted of a number of elements that included review of routinely collected data, observed clinical care and a safety questionnaire. The methodology used to apply this process is described. Results The outcomes of 33 clinical area safety assessments (CASA) are reported. No department was awarded unconditional accreditation nor have any had their service suspended. A number of recurrent issues emerged, the most common being that 31% of departments failed to fully comply with Trust requirements for governance and 12% needed to improve compliance with patient safety standards. Concerns related to documentation were identified in 11% of assessments. To date the programme has cost approximately £111,000 with each review requiring approximately 130 hrs to complete. Conclusions The CASA programme has offered an opportunity to improve standardisation in governance and optimise safety processes across our hospital. It has facilitated the dissemination of good practice amongst teams to resolve common problems. Suggestions as to how we plan to further refine this peer review process are offered.

Truncated Robust Distance for Clinical Laboratory Safety Data Monitoring and Assessment

Laboratory safety data are routinely collected in clinical studies for safety monitoring and assessment. We have developed a truncated robust multivariate outlier detection method for identifying subjects with clinically relevant abnormal laboratory measurements. The proposed method can be applied to historical clinical data to establish a multivariate decision boundary that can then be used for future clinical trial laboratory safety data monitoring and assessment. Simulations demonstrate that the proposed method has the ability to detect relevant outliers while automatically excluding irrelevant outliers. Two examples from actual clinical studies are used to illustrate the use of this method for identifying clinically relevant outliers.

Role of mixed ion channel effects in the cardiovascular safety assessment of the novel anti‐MRSA fluoroquinolone JNJ‐Q2

JNJ-Q2, a novel broad-spectrum fluoroquinolone with anti-methicillin-resistant Staphylococcus aureus activity, was evaluated in a comprehensive set of non-clinical and clinical cardiovascular safety studies. The effect of JNJ-Q2 on different cardiovascular parameters was compared with that of moxifloxacin, sparfloxacin and ofloxacin. Through comparisons with these well-known fluoroquinolones, the importance of effects on compensatory ion channels to the cardiovascular safety of JNJ-Q2 was investigated. JNJ-Q2 and comparator fluoroquinolones were evaluated in the following models/test systems: hERG-transfected HEK293 cells sodium channel-transfected CHO cells, guinea pig right atria, arterially perfused rabbit left ventricular wedge preparations and in vivo studies in anaesthetized guinea pigs, anaesthetized and conscious telemetered dogs, and a thorough QT study in humans. The trend for effects of JNJ-Q2 on Tp-Te, QT, QRS and PR intervals in the non-clinical models and the plateau in QTc with increasing plasma concentration in humans are consistent with offsetting sodium and calcium channel activities that were observed in the non-clinical studies. These mixed ion channel activities result in the less pronounced or comparable increase in QTc interval for JNJ-Q2 compared with moxifloxacin and sparfloxacin despite its greater in vitro inhibition of I(Kr). Based on the non-clinical and clinical cardiovascular safety assessment, JNJ-Q2 has a safe cardiovascular profile for administration in humans with comparable or reduced potential to prolong QT intervals, compared with moxifloxacin. The results demonstrate the importance of compensatory sodium and calcium channel activity in offsetting potassium channel activity for compounds with a fluoroquinolone core.

Tuberculin skin test and BCG scar in children vaccinated at birth: a study from Iran

investigations and pre-clinical and clinical safety studies, may help to make informed decisions in clinical practice. Methods: Pre-clinical toxicology and clinical safety assessments, both within the context of controlled clinical trials and post-marketing surveillance, are conducted for all licensed vaccines. In addition pre-clinical adjuvant MoA studies provide additional information regarding the safety profile of novel adjuvanted vaccines. Our discussion will focus on the added support that MoA studies bring to the safety evaluation of adjuvanted vaccines. As an example of MoA and safety data wewill use the results of studies with the AS04-adjuvanted L1/16&18 HPV vaccine. Results: The preclinical toxicology package of the AS04adjuvanted L1/16&18 HPV vaccine has not shown treatmentrelated toxicologyfindings other than local injection site inflammation. MoA data showed that AS04 induced a transient and localised activation of innate cells at the injection site and in the local draining lymph nodes, with no systemic impact or direct effect on T cells and B-cellls. Clinical safety evaluation and follow-up in a trial setting have shown no clinically relevant differences compared with control groups other than reactogenicity, mostly at local level, consistent with findings from preclinical data and MoA studies. Finally, with more than 25 million doses distributed worldwide, post-licensure safety evaluations have shown adverse events consistent with what has been observed in the clinical development program, with most commonly reported events being local site reactions of short duration (2-3 days). Conclusion:Regulatory authorities require rigorouspre-clinical and clinical safety data to determine the benefit/risk profile of new vaccines. Post-licensure, a continuous pharmacovigilance system is in place to further assess vaccine safety. Research studying the mechanism of action of an adjuvanted vaccine can help to further investigate the vaccine’s safety profile.

Abstract 756: Pharmacokinetics of curcumin and curcumin O-glucuronide in healthy volunteers characterized by liquid chromatography-tandem mass spectrometry

Abstract Purpose: To develop and validate a liquid chromatography-tandem mass spectrometric method (LC-MS/MS) for simultaneous quantification of curcumin and curcumin O-glucuronide (COG) in human plasma, and to characterize the pharmacokinetics (PK) of curcumin and COG in healthy volunteers after separate oral administrations of Curcumin C3 Complex (CC3C) and nano-emulsion Curcumin (NEC) using this method. Methods: The study was conducted at The Ohio State University (OSU) with the approval of the OSU Institutional Review Board. CC3C and NEC were administered orally to four healthy volunteers and plasma levels of curcumin and COG were determined by a validated LC-MS/MS method. The pharmacokinetic parameters were calculated using WinNonlin computer software. Clinical safety assessment included vital signs and biochemical measurement on the day of each PK study and three weeks following each PK study to monitor potential toxicity. A mixed effect model was used for comparing the concentration of curcumin or COG at each time point after the oral consumption of CC3C or NEC across each donor using SAS 9.2 software. Results: An LC-MS/MS method for simultaneous quantification of curcumin and COG in human plasma with the lower limit of quantification of 2 ng/mL was established. The within-day and between-day validation parameters were consistent with the Food and Drug Administration's (FDA) criteria for Good Laboratory Practice analytical methods. A cross-over pharmacokinetic study in the four healthy volunteers revealed that 2g NEC delivered much higher plasma concentrations of free curcumin (1.5-8.0 ng/mL vs. non-detectable, p<0.001, paired t-test) and COG (550-3300 ng/mL vs. 3.0-167 ng/mL, p<0.05, paired t-test) when compared to 4g of CC3C. The total drug exposure of curcumin and COG from NEC in human volunteers is 26 to 350-fold higher than that of CC3C. No adverse events were noted following administrations of CC3C and NEC. No abnormalities were noted on the hematologic, clinical chemistry, and metabolic profiles at prescreening, and at 3 weeks following CC3C and NEC administration. Conclusion: NEC represents a novel formulation of curcumin with enhanced oral absorption of curcumin and is worthy of evaluation for future clinical applications. Supported by NIH-NCI-R21 CA135478 [ZL], UL1RR025755 [NCRR] and the BioMedical Mass Spectrometry Laboratory [KC & ZL]. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 756. doi:1538-7445.AM2012-756

The Effect of Definity on Systemic and Pulmonary Hemodynamics in Patients

The purpose of this study was to evaluate the pulmonary and systemic hemodynamic effects of Definity in patients with normal as well as those with elevated pulmonary artery pressure at baseline. Secondary objectives of the study were to evaluate safety and determine whether any potential immunologic reactions develop after Definity administration. Patients with normal and elevated pulmonary artery systolic pressure undergoing right-heart catheterization received Definity (10 μL/kg) as a slow bolus over 30 to 60 sec. Multiple sequential measurements of right atrial pressure, pulmonary artery systolic pressure, pulmonary artery diastolic pressure, mean pulmonary artery pressure, cardiac output, and pulmonary capillary wedge pressure were made before and after Definity administration. Vital signs, electrocardiograms, and blood samples were taken at multiple time points. Patients were followed for the development of adverse events. A total of 32 patients (16 with elevated pulmonary artery systolic pressure > 35 mm Hg) were enrolled. No significant changes in any pulmonary or systemic hemodynamic parameters, vital sign values, electrocardiographic data, or laboratory variables were found for data obtained before versus after receipt of Definity. The administration of Definity at the approved dosage does not change pulmonary or systemic hemodynamics in control patients or those with mild to moderate pulmonary hypertension. No significant changes were noted in a wide array of clinical and laboratory safety assessments after patients were exposed to Definity.

Bioethical issues in the development of biopharmaceuticals

Development of biopharmaceuticals is a challenging issue in bioethics. Unlike conventional, small molecular weight drugs, biopharmaceuticals are proteins derived from DNA technology and hybrid techniques with complex three dimensional structures. Immunogenicity of biopharmaceuticals should always be tested in clinical settings due to low predictive value of preclinical animal models. However, non-human primates (NHP) and transgenic mice could be used to address certain aspects of immunogenicity. Substantial efforts have been made to reduce NHP use in biopharmaceutical drug development, e.g. study design improvements and changes in regulatory policy. In addition, several expert groups are active in this field (e.g. NC3Rs, BioSafe, and Biopharmaceutical Technical Group). Despite that, there is an increasing trend of use of NHP in preclinical safety testing of biopharmaceuticals, especially regarding monoclonal antibodies. Other potential bioethical issues related biopharmaceutical drug development are their cost/effectiveness ratio, clinical safety assessment, production of biosimilars, and comparison of their efficacy with placebo in countries without intention to market. Identification of the human genome has opened many new bioethical issues. Development of biopharmaceuticals is an important bioethical issue for several reasons. It connects all aspects of contemporary bioethics: bio?medicine (e.g. clinical trials in vulnerable subjects), animal welfare and the most recent ad?vances in biotechnology. In particular, biopharmaceutical drug development is a challenging issue regarding treatment of rare diseases.

Toxicokinetics of naringin and its metabolite naringenin after 180-day repeated oral administration in beagle dogs assayed by a rapid resolution liquid chromatography/tandem mass spectrometric method

Toxicokinetic characteristics of naringin and its metabolite naringenin were investigated in beagle dogs after oral administration of naringin at the doses of 20, 100, or 500 mg/kg/day in a repeated-dose study for 1, 30, 90, and 180 days. Plasma concentrations of naringin and naringenin were determined by a rapid resolution liquid chromatography/electrospray ionization/tandem mass spectrometric method. The results showed that no differences in systemic exposure were observed between male and female beagle dogs. Systematic exposure exhibited dose-dependent increase for both naringin and naringenin. No significant accumulations were observed. Results would be taken into consideration for the interpretation of toxicology findings and provide a reference for clinical safety assessment.

Statistical aspects in comparative benefit-risk assessment: challenges and opportunities for pharmaceutical statisticians

Benefit-risk assessment is a fundamental element of drug development with the aim to strengthen decision making for the benefit of public health. Appropriate benefit-risk assessment can provide useful information for proactive intervention in health care settings, which could save lives, reduce litigation, improve patient safety and health care outcomes, and furthermore, lower overall health care costs. Recent development in this area presents challenges and opportunities to statisticians in the pharmaceutical industry. We review the development and examine statistical issues in comparative benefit-risk assessment. We argue that a structured benefit-risk assessment should be a multi-disciplinary effort involving experts in clinical science, safety assessment, decision science, health economics, epidemiology and statistics. Well planned and conducted analyses with clear consideration on benefit and risk are critical for appropriate benefit-risk assessment. Pharmaceutical statisticians should extend their knowledge to relevant areas such as pharmaco-epidemiology, decision analysis, modeling, and simulation to play an increasingly important role in comparative benefit-risk assessment.

“Early Clinical Assessment Of Feasibility And Safety In Flattering Filter Free (FFF) Based Stereotactic Body Radiotherapy (SBRT) Treatments”

“Early Clinical Assessment Of Feasibility And Safety In Flattering Filter Free (FFF) Based Stereotactic Body Radiotherapy (SBRT) Treatments”

Antivenoms for Snakebite Envenomings

Animal-derived antivenoms constitute the mainstay in the therapy of snakebite envenoming. Antivenoms are manufactured by immunizing animals, usually horses, with venoms from a single or several medically-relevant snake species. Antivenoms are constituted by either whole IgG molecules or the immunoglobulin fragments F(ab')₂ and Fab, obtained by digestion with pepsin and papain, respectively. Differences in the pharmacokinetics of these active substances have pharmacodynamic implications. Novel technological possibilities may improve the quality of antivenoms in the future, as well as their microbial safety. Antivenom administration might induce early and late adverse reactions, whose possible mechanisms are discussed. Owing to the large variety in the composition of snake venoms and to the need to demonstrate neutralization of relevant snake venoms in different countries, a meticulous preclinical and clinical assessment of antivenom efficacy and safety is required before an antivenom is introduced into clinical application. The accessibility of antivenoms in low-income tropical countries is of concern and efforts should be directed at guaranteeing the access of safe and effective antivenoms at affordable prices and their correct clinical use in these countries.

Causality assessment of serious neurologic adverse events following 2009 H1N1 vaccination

Adverse events occurring after vaccination are routinely reported to the Vaccine Adverse Event Reporting System (VAERS). We studied serious adverse events (SAEs) of a neurologic nature reported after receipt of influenza A (H1N1) 2009 monovalent vaccine during the 2009-2010 influenza season. Investigators in the Clinical Immunization Safety Assessment (CISA) network sought to characterize these SAEs and to assess their possible causal relationship to vaccination. Centers for Disease Control and Prevention (CDC) and Food and Drug Administration (FDA) physicians reviewed all SAE reports (as defined by the Code of Federal Regulations, 21CFR§314.80) after receipt of H1N1 vaccine reported to VAERS between October 1, 2009 and March 31, 2010. Non-fatal SAE reports with neurologic presentation were referred to CISA investigators, who requested and reviewed additional medical records and clinical information as available. CISA investigators assessed the causal relationship between vaccination and the event using modified WHO criteria as defined. 212 VAERS reports of non-fatal serious neurological events were referred for CISA review. Case reports were equally distributed by gender (50.9% female) with an age range of 6 months to 83 years (median 38 years). The most frequent diagnoses reviewed were: Guillain-Barré Syndrome (37.3%), seizures (10.8%), cranial neuropathy (5.7%), and acute disseminated encephalomyelitis (3.8%). Causality assessment resulted in classification of 72 events as "possibly" related (33%), 108 as "unlikely" related (51%), and 20 as "unrelated" (9%) to H1N1 vaccination; none were classified as "probable" or "definite" and 12 were unclassifiable (6%). The absence of a specific test to indicate whether a vaccine component contributes to the pathogenesis of an event occurring within a biologically plausible time period makes assessing causality difficult. The development of standardized protocols for providers to use in evaluation of adverse events following immunization, and rapid identification and follow-up of VAERS reports could improve causality assessment.