Drug Safety Studies Research Articles

Drug‐induced hepatic injury in children: a case/non‐case study of suspected adverse drug reactions in VigiBase

To identify which drugs are associated with reports of suspected hepatic injury in children and adolescents. Using a worldwide pharmacovigilance database, VigiBase, we conducted a case/non-case study on suspected adverse drug reactions (ADRs) occurring in the population <18 years old. Cases were all the records with hepatic ADRs and non-cases were all the other ADR records. Records regarding topically administered drugs were excluded from both groups. The association between drug and suspected hepatic ADRs was calculated using the reporting odds ratio (ROR) as a measure of disproportionality while adjusting for gender, country, reporter and calendar year. Sub-analyses were performed within therapeutic class and by excluding vaccination-related reports to reduce confounding. Overall, 6595 (1%) out of 624 673 ADR records in children and adolescents concerned hepatic injury. Most of the reported hepatic injuries concerned children 12-17 years of age. Drugs that were most frequently reported as suspected cause and were associated with hepatic injury comprised paracetamol, valproic acid, carbamazepine, methotrexate, minocycline, zidovudine, pemoline, ceftriaxone, bosentan, ciclosporin, atomoxetine, olanzapine, basiliximab, erythromycin and voriconazole. The association between hepatotoxicity and all these drugs, except for basiliximab, is already known. Drug-induced hepatic injury is infrequently reported (only 1% of total) as a suspected ADR in children and adolescents. The drugs associated with reported hepatotoxicity (paracetamol, antiepileptic and anti-tuberculosis agents) are known to be hepatotoxic in adults as well, but age related changes in associations were observed. VigiBase is useful as a start to plan further drug safety studies in children.

Overview of the FDA Amendments Act of 2007: Its Effect on the Drug Development Landscape

The Food and Drug Administration Amendments Act of 2007 has improved the transparency of the clinical drug development landscape in the United States in many ways. Some of the important changes require: (a) increased public disclosure of information on clinical trials both while being conducted and during the subsequent public disclosure of the results of the trial; (b) changes to the required labeling including the development of a Risk Evaluation and Mitigation Strategy (REMS) to ensure that the benefits of the product outweigh its risks in the target population; (c) a requirement to do additional drug safety studies when indicated based on the available safety data; and (d) a requirement for the performance of pediatric studies when the drug may have a potential to provide better treatment options for pediatric subjects and subsequent revision of the labeling based on pediatric studies. The act has also increased FDA's authority to mandate necessary changes.

Veterinary and toxicological applications for the detection of cardiac injury using cardiac troponin

The use of cardiac troponin (cTn), the 'gold-standard' biomarker of myocardial injury in humans, is growing in veterinary medicine and in animal safety studies, although there are differences in its application in animals. In this study six new assays for the marker were assessed in 619 animals of six different species (dog, cat, horse, cattle, rat and rabbit), in clinical and drug-safety studies. Healthy animals and clinical cases without cardiac disease served as controls. Several of the tested assays had poor analytic or diagnostic sensitivity and only one test was effective in all species and in all models of cardiac injury. This assay had the highest sensitivity and widest dynamic range, and identified cardiac injury due to anaemia, pancreatitis, uncontrolled Addison's and Cushing's disease, old age, renal disease, severe colic, lymphoma and neoplasia. Detection of the cTnI and cTnT forms correlated with loss of cardiac function in toxicity studies in rodents and rabbit. Increased serum cTnI was not found to correlate with disease aetiology or pathogenesis, but was effective in detecting, monitoring and quantifying ongoing cardiac injury. Cardiac injury, as demonstrated by elevated cTnI in blood, appears to be a common sequel to a wide variety of both primarily cardiac disease and of other diseases that do not primarily involve the cardiovascular system.

Instrumental variable methods in comparative safety and effectiveness research

Instrumental variable (IV) methods have been proposed as a potential approach to the common problem of uncontrolled confounding in comparative studies of medical interventions, but IV methods are unfamiliar to many researchers. The goal of this article is to provide a non-technical, practical introduction to IV methods for comparative safety and effectiveness research. We outline the principles and basic assumptions necessary for valid IV estimation, discuss how to interpret the results of an IV study, provide a review of instruments that have been used in comparative effectiveness research, and suggest some minimal reporting standards for an IV analysis. Finally, we offer our perspective of the role of IV estimation vis-à-vis more traditional approaches based on statistical modeling of the exposure or outcome. We anticipate that IV methods will be often underpowered for drug safety studies of very rare outcomes, but may be potentially useful in studies of intended effects where uncontrolled confounding may be substantial.

Multivariate-adjusted pharmacoepidemiologic analyses of confidential information pooled from multiple health care utilization databases.

Mandated post-marketing drug safety studies require vast databases pooled from multiple administrative data sources which can contain private and proprietary information. We sought to create a method to conduct pooled analyses while keeping information private and allowing for full confounder adjustment. We propose a method based on propensity score (PS) techniques. A set of propensity scores are computed in each data-contributing center and a PS-adjusted analysis is then carried out on a pooled basis. The method is demonstrated in a study of the potentially negative effects of concurrent initiation of clopidogrel and proton pump inhibitors (PPIs) in four cohorts of patients assembled from North American claims data sources. Clinical outcomes were myocardial infarction (MI) hospitalization and hospitalization for revascularization procedure. Success of the method was indicated by equivalent performance of our PS-based method and traditional confounder adjustment. We also implemented and evaluated high-dimensional propensity scores and meta-analytic techniques. On both a pooled and individual cohort basis, we saw substantially similar point estimates and confidence intervals for studies adjusted by covariates and from privacy-maintaining propensity scores. The pooled, adjusted OR for MI hospitalization was 1.20 (95% confidence interval 1.03, 1.41) with individual variable adjustment and 1.16 (1.00, 1.36) with PS adjustment. The revascularization OR estimates differed by < 1%. Meta-analysis and pooling yielded substantially similar results. We observed little difference in point estimates when we employed standard techniques or the proposed privacy-maintaining pooling method. We would recommend the technique in instances where multi-center studies require both privacy and multivariate adjustment.

Human and Murine Embryonic Stem Cell-Derived Cardiomyocytes Serve Together as a Valuable Model for Drug Safety Screening

Aims: Screening of drug safety is typically performed in diverse non-human healthy species with an intact repolarization reserve. Nevertheless, these drugs are later applied in diseased humans with a reduced repolarization reserve. It would be optimal to set up a preclinical screening tool to estimate the proarrhythmic potential of drugs in human cardiac tissue with a reduced repolarization reserve in vitro. Methods and Results: In our study spontaneously beating human embryonic stem cell-derived cardiomyocytes clusters (hESCM) and murine ES cell-derived cardiomyocytes (mESCMs) were plated onto micro-electrode arrays (MEAs) to record the extracelluar field potentials (FPs) as well as effects of several antiarrhythmic drugs. In line with clinical observations the class III antiarrhythmic drugs (±)-sotalol, E4031 and class I antiarrhythmic drug quinidine led to a prolongation of the cardiac repolarization phase (FP duration, FPdur) and a decrease of the FP frequency. Verapamil (a class IV antiarrhythmic drug) decreased the FP frequency and shortened FPdur. Both, quinidine and verapamil, but not (±)-sotalol or E4031 decreased conduction velocities in hESCM clusters. Moreover, (±)-sotalol exerted stronger effects on FPdur in early developmental stages of hESCMs, as proof for a reduced repolarization reserve. The EC₅₀ of the (±)-sotalol-induced prolongation of the FPdur was higher in mESCMs than in hESCMs implying species-dependent differences in cardiac repolarization. Likewise, the incidence of drug-induced early recurrent depolarization (ERDs) was higher in mESCMs than hESCMs. Conclusion: The combined measurement of drug effects on FP parameters in hESCMs and mESCMs serves as a reliable in vitro model for preclinical studies of drug safety.

Herpesvirus infections of laboratory macaques

Non-human primates (NHPs), primarily macaques, are commonly used as non-rodent species in pre-clinical safety assessment studies. The use of macaques in such studies is increasing largely due to the development of biopharmaceutical and immunomodulatory therapies that necessitates extensive safety testing. Macaques, commonly available for use in such studies, are infected by a rich flora of herpesviruses that cause persistent, latent, life-long infections. Primary infection of immune competent macaques is typically subclinical with very little associated morbidity and mortality only in very rare cases. A life-long consequence of herpesvirus infection is periodic stochastic and frequently asymptomatic recurrences from latency throughout an infected macaque’s lifetime. With immune modulation or suppression, however, immune control of herpesvirus infections can be lost, resulting in significant disease and even death of the affected animals. Since macaques undergo primary infection with herpesviruses starting around 4-6 months-of-age when maternally-derived antibody begins to wane, it is difficult and costly to derive animals that are herpesvirus-free. Further, the herpesvirus flora and prevalence of infection in laboratory macaques mirrors that of the adult human population making the herpesvirus-infected macaque a reasonable model of the general human population. This review is intended to familiarize toxicologists performing preclinical drug safety studies with the basic biology, disease pathogenesis and consequences of immune suppression in herpesvirus-infected laboratory macaques.

Malaria management - progress made and challenges still to face

Malaria management - progress made and challenges still to face

Clinical veterinarian’s perspective of non-human primate (NHP) use in drug safety studies

Owing to their size, cost, and availability, the cynomolgus macaque (Macaca fascicularis) has surpassed the rhesus macaque in its use as a non-human primate preclinical model for drug safety studies. There are three major regions where cynomolgus macaques are bred: China, Southeast Asia, and the island of Mauritius. Country of origin of the macaque is important, as disease status and background disease incidence in non-human primates from each of these sites can differ. Once a source of macaque has been decided, careful monitoring of the animal during breeding and by the importing vendor while the animals are in quarantine is important. During vendor quarantine, the animals should be monitored and evaluated for disease, response to tuberculosis testing, retroviral status, and both ecto- and endoparasites. After animals arrive at the test facility, additional quarantine and acclimation are important to ascertain health status further and to reduce stress on the animals, thereby providing a better research model. The type of caging, food, water, and enrichment should be carefully selected to best suit the needs of the study while working within Federal Regulations (i.e., Animal Welfare Act and Good Laboratory Practices). Careful prescreening by performing tests (such as physical, neurologic, and ophthalmologic examinations), complete blood count, biochemical profile, urinanalysis, electrocardiograms, and pulse oximetry is important when selecting the most appropriate animals for the study. After the in-life portion of the study begins, animals that present with clinical signs should be examined and an appropriate treatment course begun while maintaining study objectives. As many commonly used medications have immunomodulatory effects, having an understanding of the mechanism of action of test articles will aid in the appropriate choice of treatment of study animals. A tiered approach to the treatment of these animals is a conservative and usually acceptable approach.

Phynx: an open source software solution supporting data management and web‐based patient‐level data review for drug safety studies in the general practice research database and other health care databases

To develop a software solution that supports management and clinical review of patient data from electronic medical records databases or claims databases for pharmacoepidemiological drug safety studies. We used open source software to build a data management system and an internet application with a Flex client on a Java application server with a MySQL database backend. The application is hosted on Amazon Elastic Compute Cloud. This solution named Phynx supports data management, Web-based display of electronic patient information, and interactive review of patient-level information in the individual clinical context. This system was applied to a dataset from the UK General Practice Research Database (GPRD). Our solution can be setup and customized with limited programming resources, and there is almost no extra cost for software. Access times are short, the displayed information is structured in chronological order and visually attractive, and selected information such as drug exposure can be blinded. External experts can review patient profiles and save evaluations and comments via a common Web browser. Phynx provides a flexible and economical solution for patient-level review of electronic medical information from databases considering the individual clinical context. It can therefore make an important contribution to an efficient validation of outcome assessment in drug safety database studies.

Exploratory drug safety: A discovery strategy to reduce attrition in development

Identification of novel new molecules which hold the greatest promise of safe and effective therapies remains a continuous challenge to the pharmaceutical industry. This has led the industry to implement strategies for identification of the most promising candidates during the discovery phase and for their safe and expeditious advancement through development. Testing for potential liable properties in the discovery phase has included the evaluation of major areas of pharmaceutics that have led to failure such as its physical and pharmaceutical properties, drug metabolism and pharmacokinetic characteristics, various safety endpoints including pre-development safety pharmacology, general toxicology and genetic toxicology and interrogation of counter-screen data to identify off-target affinities (i.e., receptors, ion channels, transporters, kinases, etc.) that pose a concern. Amongst the many important areas of concern is the potential for toxicities of the major organ systems. To mitigate this concern, a strategy pursued is to identify the prominent toxicological properties of the candidate prior to its recommendation for development. The results of these studies in discovery allow exclusion of the candidate before the expenditure of resources and time typical of development. In addition, the discovery phase toxicology studies serve to address key questions that may have arisen from the study of another molecule, the phenotypic profile from pre-clinical models where the therapeutic target has been genetically modified or concerns that have been raised as a result of other investigations. Importantly, the results of the exploratory drug safety studies will be used by the sponsor to judge the potential risks associated with continued pursuit of a potential development candidate. In many ways, pre-clinical toxicological investigations in discovery serve the important objective of identifying the most promising candidates to progress into development and onto registration.

Comparison of QTinno, a fully automated electrocardiographic analysis program, to semiautomated electrocardiographic analysis methods in a drug safety study in healthy subjects

Background Improved automated methods for electrocardiographic (ECG) analysis are needed, particularly for drug development purposes. Objectives This study compared a novel fully automated method for ECG analysis (QTinno; NewCardio, Santa Clara, CA) to 2 semiautomated digital methods: global measurement from the earliest QRS onset to the latest T-wave offset on representative superimposed beats (global) and tangent measurement on 3 consecutive beats in one lead (tangent). Methods All 3 methods were used to determine uncorrected and rate-corrected QT interval duration (QT and QTcF) and related metrics in 1422 digital 12-lead ECGs from a phase 1 drug study. Global and tangent annotations were manually adjusted by the same 3 cardiologists wherever necessary. No adjustments were made in QTinno determinations. Results QTinno returned QTcF change from time-matched baseline (ΔQTcF) that differed minimally from both global and tangent methods (mean pairwise difference: 0.1 millisecond between QTinno and global, 1.1 milliseconds between QTinno and tangent). The average absolute QT and QTcF intervals by QTinno were approximately 5 milliseconds longer than global and 25 milliseconds longer than by tangent. QTinno had lower intrinsic variability for ΔQTcF than either global or tangent (between-subject SD: QTinno 4.0 milliseconds, global 5.6 milliseconds, tangent 6.4 milliseconds; within-subject SD: QTinno 4.8 milliseconds, global 7.4 milliseconds, tangent 10.6 milliseconds). All methods were robust in detecting the largest placebo-adjusted mean time-matched ΔQTcF (15-25 milliseconds) induced by study drug. Conclusions The methods show good agreement for drug-induced QTc prolongation. Lower intrinsic variability of ΔQTcF by QTinno could facilitate smaller sample sizes or increase study power in thorough QTc studies.

Canine Cardiac Rhabdomyoma

A well-circumscribed, expansile, and nonencapsulated cardiac rhabdomyoma composed of tightly arranged, large, variably sized, ovoid to irregular, swollen myocytes with deeply eosinophilic cytoplasm and varying degrees of cytoplasmic vacuolation was detected in an eight- to nine-month-old female beagle dog in a routine toxicology study. By histochemistry, the neoplasm was periodic acid-Schiff positive. By immunohistochemistry (IHC), neoplastic cells were positive for desmin and myoglobin and negative for vimentin and smooth muscle actin. Spontaneous lesions in the heart of young beagle dogs are rare in drug safety studies. On the basis of histopathology, histochemistry, and IHC findings, a diagnosis of cardiac rhabdomyoma was made. Cardiac rhabdomyoma is one of the most frequently occurring primary tumors of the heart and, by far, the most common neoplasm in human infants and children. To our knowledge, this is the first report of the canine cardiac rhabdomyoma.

Instrumental Variable Analysis for Estimation of Treatment Effects With Dichotomous Outcomes

Instrumental variable analyses are increasingly used in epidemiologic studies. For dichotomous exposures and outcomes, the typical 2-stage least squares approach produces risk difference estimates rather than relative risk estimates and is criticized for assuming normally distributed errors. Using 2 example drug safety studies evaluated in 3 cohorts from Pennsylvania (1994-2003) and British Columbia, Canada (1996-2004), the authors compared instrumental variable techniques that yield relative risk and risk difference estimates and that are appropriate for dichotomous exposures and outcomes. Methods considered include probit structural equation models, 2-stage logistic models, and generalized method of moments estimators. Employing these methods, in the first study the authors observed relative risks ranging from 0.41 to 0.58 and risk differences ranging from -1.41 per 100 to -1.28 per 100; in the second, they observed relative risks of 1.38-2.07 and risk differences of 7.53-8.94; and in the third, they observed relative risks of 1.45-1.59 and risk differences of 3.88-4.84. The 2-stage logistic models showed standard errors up to 40% larger than those of the instrumental variable probit model. Generalized method of moments estimation produced substantially the same results as the 2-stage logistic method. Few substantive differences among the methods were observed, despite their reliance on distinct assumptions.

Databases for pediatric medicine research in Europe—assessment and critical appraisal

To identify and describe European health care databases that can be used for pediatric pharmacoepidemiological research. A web-based survey was conducted among all European databases that were listed on the website of the International Society of Pharmacoepidemiology (ISPE) and/or known by an expert group. The survey comprised of questions regarding (a) the nature of the database, (b) database size, (c) demographic, clinical and drug related data provided, (d) cost, and (e) accessibility of the database. A total of 25 data sources from 12 European countries were identified and invited to participate in the survey. Responses were obtained from 21 (84%) databases located in 10 different European countries. Seventeen databases were included in the assessment comprising a total of at least 9 million children aged 0-18 years. The majority of databases are based on outpatient data and all keep either prescription or drug dispensing data. Ten databases are based on electronic patient records from primary care physicians and five databases are predominantly claims oriented. Three databases do not belong to either of the above mentioned categories. Almost all of the databases can be used for pediatric drug utilization studies. For drug safety studies it is more appropriate to use electronic patient record databases because of the available clinical information and the potential to obtain additional information. There are many European healthcare databases providing an enormous potential for pediatric pharmacoepidemiological research. Future research should focus on methods to bring data from different databases together to use the full capacity effectively.

PRESCRIPTION MEDICATION SHARING

In their survey of prescription medication sharing, Goldsworthy et al.1 appropriately noted the paucity of information on this important behavior. Given concerns about potentially harmful effects on the fetus from in utero exposures to medication, it is particularly important to understand medication-sharing behaviors among a broad sample of pregnant women. We examined this question some time ago. A performer participates in the second Walk Against Children's Malnutrition and Hunger in El Salvador, organized by the World Food Programme of the United Nations in the face of the global food crisis. Photograph by Jose Cabezas/AFP/Getty Images. Printed with permission. In the early days of our current case–control surveillance study of birth defects in relation to medication use in pregnancy,2 we evaluated the effect of questionnaire design on recall of medication use. As part of that analysis, we summarized data from interviews conducted between 1976 and 1984 involving 5435 mothers who delivered malformed or nonmalformed infants in geographic areas surrounding Boston, Massachusetts; Philadelphia, Pennsylvania; Toronto, Ontario; and in part of Iowa. Interviews were conducted within 6 months of delivery, and included questions about use in pregnancy of 9 specifically named prescription medications. Women who answered affirmatively to any of those drugs were asked whether these medications were obtained from physicians or from other sources, such as friends, neighbors, or relatives.3 Among users of Bendectin, Fiorinal, Hydrodiuril, Clomid, and Seconal, less than 5% reported a source other than a physician; however, higher proportions reported nonphysician sources for Compazine (9%), Diuril (11%), Valium (18%), and Darvon (22%). Goldsworthy et al.1 correctly noted a number of consequences of medication-sharing behaviors, to which we would add an additional consequence: pharmacoepidemiology studies of drug safety increasingly rely on exposure information drawn from computerized prescription or pharmacy records (often as part of HMO or claims data). Our earlier conclusion, now supported by the work of Goldsworthy et al., is therefore even more relevant today: [I]n addition to concern that [information from such sources] includes false positive ‘exposures’—prescriptions issued or filled but not consumed—our findings suggest that these data sources may also include appreciable numbers of false negative exposures—drugs consumed but obtained from nonidentified sources.3(p675) Appreciable exposure misclassification would have very serious consequences when it comes to using prescription data sources to identify adverse effects of medication exposures; any such efforts must take into consideration the extent to which studied medications are shared.

Histologic Processing of the Eye for Obtaining the Macular Region of the Retina of the Cynomolgus Monkey

Microscopic evaluation of the macular region of the retina is essential in preclinical drug safety studies in cynomolgus monkeys. A number of therapeutic agents are suspected of causing damage to the macula in humans; therefore, the macular region of the retina should be evaluated in preclinical drug safety studies in monkeys. Histopathologic examination of the fovea may be required for preclinical drug safety evaluation of certain ocular drugs for human risk assessment. Using the inferior oblique muscle as a landmark, the macula including the fovea was obtained in 100% of 20 eye sections. It is easier to obtain just the macular region of the retina than the fovea in the section. Measurements for the inferior oblique muscle (point of insertion), fovea, macula, and the optic disc for 20 eyes of untreated cynomolgus monkeys were taken. In the cynomolgus monkey, the macula was 2.01 mm in diameter and the fovea was 0.53 mm in diameter. The distance from the center of the optic disc to the center of the fovea was 3.23 mm. In the fixed eyes, the point of insertion of the inferior oblique muscle to the sclera was 5.96 mm. (The J Histotechnol 31:113, 2008)Submitted January 7, 2008; accepted with revisions June 22, 2008

The FDA Drug Safety Bill: how safe are our drugs?

The world of drug safety is undergoing major changes in the US, Europe and elsewhere following several major drug withdrawals, billion dollar lawsuits, NGO studies of drug safety and widespread media attention in the US. Some of the events of the past few years are reviewed along with some of the reactions and changes in the FDA and the field of drug safety followed by the author's conclusions and views on the future of drug safety.

Individual case safety reports in children in commonly used drug groups – signal detection

BackgroundDue to few paediatric drug safety studies, knowledge on risks of drug treatment in children is limited. The knowledge needs to be increased to make proper risk-benefit analyses possible when treating paediatric patients with drugs. The aim of the present study was to investigate drug groups commonly used in children concerning type and frequency of individual case safety reports in children.MethodsNumber and type of individual case safety reports in the 30 groups of drugs (5th level ATC-code) most sold (number of defined daily doses) in outpatient treatment to children (<15 years old) during 2005 were obtained. Descriptive analyses of the adverse drug reactions reported in children were performed.ResultsThe number of individual case safety reports per million defined daily doses in children varied in the groups of drug between 0 and 24. The largest number was found in the drug group R03DC, the leukotriene receptor antagonist montelukast; the majority of the children being <5 years old and experiencing psychiatric adverse drug reactions.ConclusionThe number of individual case safety reports per million defined daily doses varies in different groups of drugs. A possible signal for montelukast and psychiatric adverse drug reactions was found, which should be further explored.

Impact of Infections and Normal Flora in Nonhuman Primates on Drug Development

Preclinical safety studies that are required for the marketing approval of a pharmaceutical include single and repeat dose studies in rodent and nonrodent species. The use of nonhuman primates (NHPs), primarily macaques, as the nonrodent species has increased in recent years, in part due to the increase in development of biopharmaceuticals and immunomodulatory agents. Depending on the source of the macaques, they may vary in genetic background, normal flora, and/or the incidence of preexisting pathogens and inflammatory conditions. As the use of alternative sources of macaques rises to meet the increased demand for these animals in biomedical research, the toxicologic pathologist should be well versed in NHP pathology to adequately assess potential drug-related effects in the context of these variations. Such knowledge is particularly important in studies involving immunomodulatory drugs as the toxicologic pathologist should anticipate which type(s) of infections are most likely to arise depending on which arm of the immune system is modulated. The purpose of this review is to discuss the immunosuppressive (e.g., simian type D retrovirus, simian immunodeficiency virus) and opportunistic viruses (e.g., cytomegalovirus, adenovirus, simian virus 40, rhesus rhadinovirus, and lymphocryptovirus), primary and opportunistic bacteria (e.g., Campylobacter spp., Shigella flexneri, Yersinia enterocolitica, Moraxella catarrhalis, Mycobacterium avium complex, enteropathogenic Escherichia coli), and parasites (e.g., Plasmodium spp., Schistosoma spp., Strongyloides fulleborni) that have had the most profound impact on the interpretation of drug safety studies and/or that may reemerge as alternative sources of NHPs are used for drug safety studies.