Overview of global real-world data sources for pediatric pharmacoepidemiologic research.

PURPOSE: Given limited information available on real-world data (RWD) sources with pediatric populations, this study describes features of globally available RWD sources for pediatric pharmacoepidemiologic research. METHODS: An online questionnaire about pediatric RWD sources and their attributes and capabilities was completed by members and affiliates of the International Society for Pharmacoepidemiology and representatives of nominated databases. All responses were verified by database representatives and summarized. RESULTS: Of 93 RWD sources identified, 55 unique pediatric RWD sources were verified, including data from Europe (47%), United States (38%), multiregion (7%), Asia-Pacific (5%), and South America (2%). Most databases had nationwide coverage (82%), contained electronic health/medical records (47%) and/or administrative claims data (42%) and were linkable to other databases (65%). Most (71%) had limited outside access (e.g., by approval or through local collaborators); only 10 (18%) databases were publicly available. Six databases (11%) reported having >20 million pediatric observations. Most (91%) included children of all ages (birth until 18th birthday) and contained outpatient medication data (93%), while half (49%) contained inpatient medication data. Many databases captured vaccine information for children (71%), and one-third had regularly updated data on pediatric height (31%) and weight (33%). Other pediatric data attributes captured include diagnoses and comorbidities (89%), lab results (58%), vital signs (55%), devices (55%), imaging results (42%), narrative patient histories (35%), and genetic/biomarker data (22%). CONCLUSIONS: This study provides an overview with key details about diverse databases that allow researchers to identify fit-for-purpose RWD sources suitable for pediatric pharmacoepidemiologic research.

Acute Kidney Injury During Treatment with Intravenous Acyclovir for Suspected or Confirmed Neonatal Herpes Simplex Virus Infection.

OBJECTIVE: To describe the epidemiology of and risk factors associated with acute kidney injury (AKI) during acyclovir treatment in neonates and infants. STUDY DESIGN: We conducted a multicenter (n = 4), retrospective cohort study of all hospitalized infants age <60 days treated with intravenous acyclovir (≥1 dose) for suspected or confirmed neonatal herpes simplex virus disease from January 2011 to December 2015. Infants with serum creatinine measured both before acyclovir (baseline) and during treatment were included. We classified AKI based on changes in creatinine according to published neonatal AKI criteria and performed Cox regression analysis to evaluate risk factors for AKI during acyclovir treatment. RESULTS: We included 1017 infants. The majority received short courses of acyclovir (median, 5 doses). Fifty-seven infants (5.6%) developed AKI during acyclovir treatment, with an incidence rate of AKI at 11.6 per 1000 acyclovir days. Cox regression analysis identified having confirmed herpes simplex virus disease (OR, 4.35; P = .002), receipt of ≥2 concomitant nephrotoxic medications (OR, 3.07; P = .004), receipt of mechanical ventilation (OR, 5.97; P = .001), and admission to an intensive care unit (OR, 6.02; P = .006) as risk factors for AKI during acyclovir treatment. CONCLUSIONS: Among our cohort of infants exposed to acyclovir, the rate of AKI was low. Sicker infants and those exposed to additional nephrotoxic medications seem to be at greater risk for acyclovir-induced toxicity and warrant closer monitoring.

Octreotide use and safety in infants with hyperinsulinism.

BACKGROUND: Octreotide is a synthetic peptide analog of naturally occurring somatostatin. Octreotide is used off-label in children <6 years of age for hyperinsulinism, chylothorax, and gastrointestinal bleeding. There is a lack of controlled data on efficacy or potential adverse events from this off-label use. METHODS: Three pediatric hospitals participated in this study. Patients were hospitalized January 2007-December 2010 and administered octreotide for congenital hyperinsulinism (CHI) at least 1 day. Variables assessed included octreotide dosage, patient demographics, medical interventions, concomitant medicines, serious adverse events (SAEs) including necrotizing enterocolitis (NEC), and mortality. RESULTS: The 103 patient sample had a median gestational age of 38 weeks. During the study period, two patients died: one from NEC and the other from cardiomyopathy/sepsis. There were 11 other SAEs in the 101 surviving patients. CONCLUSION: This study highlights potential risks in administering octreotide off-label. This study, like several other published studies, has highlighted NEC in a full-term infant treated with octreotide. It is important to study the efficacy and the safety of octreotide for hyperinsulinism. In the interim, it might be prudent to prescribe octreotide in CHI neonates only in the absence of other risk factors for NEC. Copyright © 2016 John Wiley & Sons, Ltd.

Pediatric registries at the Food and Drug Administration: design aspects that increase their likelihood of success.

PURPOSE: To determine aspects of the design of pediatric registries that contribute to the success of registries conducted as a postmarketing study following approval of drugs or biological products by the US Food and Drug Administration. METHODS: Pediatric registries for drugs and biological products were identified by searching the US Food and Drug Administration Postmarketing Requirements and Commitments database. Based on the recruitment of patients, the meeting of predetermined deadlines, and the submission of data, we classified studies as successful, unsuccessful, or unevaluable. Design aspects of successful and unsuccessful registries were examined for commonalities. RESULTS: Thirty-eight studies were identified, and ten registries met the criteria for successful. Four (40%) successful registries utilized a registry established prior to product approval, and six (60%) were disease-based. Among unsuccessful registries, none were disease-based or utilized a pre-existing registry. CONCLUSIONS: Characteristics identified as more common to successful registries included utilizing a disease-based registry and a registry established prior to product approval. Future studies might examine a larger sample of registries to see if these aspects consistently result in successful studies. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.

Pediatric post-marketing safety systems in North America: assessment of the current status.

PURPOSE: It is critical to have pediatric post-marketing safety systems that contain enough clinical and epidemiological detail to draw regulatory, public health, and clinical conclusions. The pediatric safety surveillance workshop (PSSW), coordinated by the Food and Drug Administration (FDA), identified these pediatric systems as of 2010. This manuscript aims to update the information from the PSSW and look critically at the systems currently in use. METHODS: We reviewed North American pediatric post-marketing safety systems such as databases, networks, and research consortiums found in peer-reviewed journals and other online sources. We detail clinical examples from three systems that FDA used to assess pediatric medical product safety. RESULTS: Of the 59 systems reviewed for pediatric content, only nine were pediatric-focused and met the inclusion criteria. Brief descriptions are provided for these nine. The strengths and weaknesses of three systems (two of the nine pediatric-focused and one including both children and adults) are illustrated with clinical examples. CONCLUSIONS: Systems reviewed in this manuscript have strengths such as clinical detail, a large enough sample size to capture rare adverse events, and/or a patient denominator internal to the database. Few systems include all of these attributes. Pediatric drug safety would be better informed by utilizing multiple systems to take advantage of their individual characteristics.

Introduction to economic assessment - part 3.

This is the third in a series of four continuing professional development articles on economic assessment. The series aims to equip readers with the knowledge and skills to apply the principles of economic assessment in practice. The series describes a tried and tested methodology that has been used by practising nurses leading service innovations. In this article, we introduce tools and templates that have been developed specifically to support nurses applying the methodology.

Introduction to economic assessment - part 4.

This is the final in a series of four continuing professional development articles on economic assessment (EA), more specifically EA in the context of nurse-led service innovation. The series aims to equip readers with an understanding of: (a) the main requirements of EA; (b) definitions of relevant terminology; (c) different EA techniques and their associated strengths and weaknesses; and (d) procedures to assign monetary values to costs and benefits. The series introduces a methodology, with associated tools and templates, that has been used by practising nurses to conduct EAs. The aim of this article is to show readers how to put monetary values on the types of cost incurred, and benefits generated, by a service innovation.

Introduction to economic assessment - part 2.

This is the second in a series of four continuing professional development articles that explain some of the principles of economic assessment (EA) and describe how they may be applied in practice by front line practitioners leading service innovations. It introduces a methodology, with associated tools and templates, that has been used by practising nurses to conduct EAs. Our purpose is to equip readers with the knowledge to develop a technically competent, pragmatic EA that will contribute towards evidence-informed decision making and assure the best use of limited resources. If you have not already read the first article in this series ( McMahon and Sin 2013), we strongly advise you to do so as each article purposefully draws and builds on those that have gone before. The time out exercises in the first article required you to access source material located on the RCN website and identify a service innovation in your workplace. The time out exercises in this article draw in these same sources. We begin this article by recapping on the points covered in the first article before exploring the implications of the principles of EA and how to apply them in practice. In this article, we refer to and draw on a companion article published in this edition of Nursing Management ( pages 38-41) that sets out the most commonly cited approaches to EA in health and social care. We aim to enable readers, along with those they seek to influence, to make an informed decision as to what may be an appropriate EA approach in any specific context.

Making the economic case for nursing innovations: horses for courses.

In economic assessment, costs must be reviewed and expressed in monetary terms. Benefits, however, may be expressed differently depending on the specific approach. This article describes the techniques that nurses are likely to come across and use most often, while emphasising that there is no single 'best' approach. Different approaches serve different purposes and the choice of approach must be based on pragmatic decision making.

Introduction to economic assessment.

This is the first in a series of four continuing professional development articles that explain some of the principles of economic assessment and describe the most commonly cited approaches. The series aims to enable readers to critically examine economic assessments in the context of nurse-led service innovation. It introduces a tried-and-tested methodology, with associated tools and templates, used to conduct economic assessments in nursing. In this article, the principles of economic assessment are introduced and two case studies of nurse-led innovation are used to illustrate how they are applied in practice.

Extrapolation of Adult Efficacy Data to Pediatric Systemic Lupus Erythematosus: Evaluating Similarities in Exposure-Response.

To streamline drug development, the United States Food and Drug Administration (FDA) can consider the extrapolation of adult efficacy data to children when the disease and drug effects are sufficiently similar. This study explored whether the relationship between drug exposure and response for selected drugs in systemic lupus erythematosus (SLE) was sufficiently similar to support a consideration of the extrapolation of adult efficacy data to children of ≥5 years of age. An exposure-response analysis of drugs used to treat SLE was conducted using published exposure versus response and efficacy versus time data. Statistical analyses included noncompartmental analysis of a drug's area under the effect curve and direct Imax pharmacodynamic (PD) modeling. Six drugs were included: azathioprine, belimumab, cyclophosphamide, hydroxychloroquine, mycophenolate/mycophenolic acid, and rituximab. For belimumab, the net change in responders at week 52 (the primary end point) was nearly identical between 1 adult trial and the pediatric trial. For mycophenolate, PD modeling suggested no significant differences in exposure and SLE disease activity between adults and children. For azathioprine, cyclophosphamide, hydroxychloroquine, and rituximab the data were not sufficient to quantitatively characterize the exposure-response relationship, but the clinical or pharmacologic response between children and adults was similar overall. Adult SLE data should be leveraged to guide pediatric drug development programs and identify areas with residual uncertainty regarding the effectiveness or safety of a drug in children. The degree to which efficacy extrapolation can reduce clinical trial requirements in pediatric SLE should be individualized for each new drug product, depending in part on the mechanism of action of the drug and the similarity of disease manifestations in children and adults.

Pediatric cardiovascular safety: challenges in drug and device development and clinical application.

Development of pediatric medications and devices is complicated by differences in pediatric physiology and pathophysiology (both compared with adults and within the pediatric age range), small patient populations, and practical and ethical challenges to designing clinical trials. This article summarizes the discussions that occurred at a Cardiac Safety Research Consortium-sponsored Think Tank convened on December 10, 2010, where members from academia, industry, and regulatory agencies discussed important issues regarding pediatric cardiovascular safety of medications and cardiovascular devices. Pediatric drug and device development may use adult data but often requires additional preclinical and clinical testing to characterize effects on cardiac function and development. Challenges in preclinical trials include identifying appropriate animal models, clinically relevant efficacy end points, and methods to monitor cardiovascular safety. Pediatric clinical trials have different ethical concerns from adult trials, including consideration of the subjects' families. Clinical trial design in pediatrics should assess risks and benefits as well as incorporate input from families. Postmarketing surveillance, mandated by federal law, plays an important role in both drug and device safety assessment and becomes crucial in the pediatric population because of the limitations of premarketing pediatric studies. Solutions for this wide array of issues will require collaboration between academia, industry, and government as well as creativity in pediatric study design. Formation of various epidemiologic tools including registries to describe outcomes of pediatric cardiac disease and its treatment as well as cardiac effects of noncardiovascular medications, should inform preclinical and clinical development and improve benefit-risk assessments for the patients. The discussions in this article summarize areas of emerging consensus and other areas in which consensus remains elusive and provide suggestions for additional research to further our knowledge and understanding of this topic.

Let the ideas flow.

Nurses often think creatively to make improvements to care, but many do not recognise this as innovation. In this article the author explains that innovation is'testing an idea in practice' and gives examples of nurse innovations. An idea does not have to be new to count as innovation, but in today's financial climate it does have to be cost-effective.

Outbreak of adverse reactions associated with contaminated heparin.

BACKGROUND: In January 2008, the Centers for Disease Control and Prevention began a nationwide investigation of severe adverse reactions that were first detected in a single hemodialysis facility. Preliminary findings suggested that heparin was a possible cause of the reactions. METHODS: Information on clinical manifestations and on exposure was collected for patients who had signs and symptoms that were consistent with an allergic-type reaction after November 1, 2007. Twenty-one dialysis facilities that reported reactions and 23 facilities that reported no reactions were included in a case-control study to identify facility-level risk factors. Unopened heparin vials from facilities that reported reactions were tested for contaminants. RESULTS: A total of 152 adverse reactions associated with heparin were identified in 113 patients from 13 states from November 19, 2007, through January 31, 2008. The use of heparin manufactured by Baxter Healthcare was the factor most strongly associated with reactions (present in 100.0% of case facilities vs. 4.3% of control facilities, P<0.001). Vials of heparin manufactured by Baxter from facilities that reported reactions contained a contaminant identified as oversulfated chondroitin sulfate (OSCS). Adverse reactions to the OSCS-contaminated heparin were often characterized by hypotension, nausea, and shortness of breath occurring within 30 minutes after administration. Of 130 reactions for which information on the heparin lot was available, 128 (98.5%) occurred in a facility that had OSCS-contaminated heparin on the premises. Of 54 reactions for which the lot number of administered heparin was known, 52 (96.3%) occurred after the administration of OSCS-contaminated heparin. CONCLUSIONS: Heparin contaminated with OSCS was epidemiologically linked to adverse reactions in this nationwide outbreak. The reported clinical features of many of the cases further support the conclusion that contamination of heparin with OSCS was the cause of the outbreak.

Tumor necrosis factor alpha blockers and malignancy in children: forty-eight cases reported to the Food and Drug Administration.

OBJECTIVE: Malignancies reported in children using tumor necrosis factor alpha (TNFalpha) blockers have raised concerns of a potential increased risk. This study was undertaken to investigate postmarketing reports of malignancy in children treated with TNF blockers. METHODS: The FDA's Adverse Event Reporting System was searched to identify malignancies associated with the use of infliximab, etanercept, and adalimumab in children in whom therapy was initiated between the ages of 0 and 18 years. The reporting rates for infliximab and etanercept were compared with the background rate of malignancy in the general pediatric population. RESULTS: Forty-eight reports of malignancy in children were identified: 31 following infliximab use, 15 following etanercept use, and 2 following adalimumab use. Half of the malignancies reported were lymphomas and included both Hodgkin's and non-Hodgkin's lymphoma. The remaining reported cases involved a variety of different malignancies including leukemia, melanoma, and solid organ cancers. The majority of the reported cases (88%) involved the concomitant use of other immunosuppressants. Reporting rates for malignancy showed that infliximab had a consistently higher reporting rate when compared with background rates in the general pediatric population for lymphomas and all malignancies. The reporting rates for etanercept were elevated above background for lymphomas and were on par with background for all malignancies. CONCLUSION: There is evidence that treatment with TNF blockers in children may increase the risk of malignancy. However, the cases were confounded by the potential risk of malignancy associated with underlying illnesses and the use of concomitant immunosuppressants; therefore, a clear causal relationship could not be established.

Methodologic approaches in studies using real-world data (RWD) to measure pediatric safety and effectiveness of vaccines administered to pregnant women: A scoping review.

OBJECTIVE: This scoping review mapped studies using real-world data (RWD) to measure pediatric safety and effectiveness of vaccines administered to pregnant women. INTRODUCTION: In the US, two vaccines are recommended for all pregnant women to prevent illness in the infant: inactivated influenza vaccine (recommended since 2004), and the combined tetanus-diphtheria-acellular pertussis (Tdap) vaccine (recommended since 2013). This scoping review maps the studies conducted to date that address questions about pediatric safety and effectiveness of vaccines administered during pregnancy and provides a knowledge base for evaluating the use of RWD to study this issue. METHODS: The scoping review was conducted following a published protocol. Methods included an electronic search of PubMed and Embase, screening of titles and abstracts by two reviewers, and double extraction of data for summary and synthesis. Studies that reported on pregnant women and the effectiveness or safety outcomes in their infants were included. RESULTS: Forty-eight studies met the inclusion criteria of the scoping review protocol using RWD to assess safety or effectiveness of influenza or pertussis vaccinations administered to pregnant women with respect to pregnancy, infant or child outcomes. Detailed information about data sources, linkage of maternal and infant data, and operational definitions for gestational age were largely absent from the majority of studies raising concerns about reproducibility and validity of study findings. CONCLUSIONS: A body of literature is available from which to plan and design future studies of vaccination in pregnant women using RWD. This is of intense importance as new vaccines, such as those for COVID-19, become available to the general population via approval or authorization without inclusion of pregnant women in the clinical trials.

Drug Safety in Labeling for Pediatric Drug Development and Dose Selection in Submissions to the US Food and Drug Administration.

Pediatric safety evaluations are an essential part of a pediatric drug development program. Communication of the results of these safety evaluations is primarily accomplished by labeling of the drug either during the initial pediatric drug development program, or during the postmarketing period after drug approval for pediatric patients. During drug development, the dose-adverse drug event (ADE) relationship is an important part of the evaluation, but a consideration for pediatric ADEs that are unrelated to drug dosage must be maintained. Examples of dose-related and non-dose-related ADEs are presented. The failure to label a product for pediatric use has been safety related for a number of development programs. The US Food and Drug Administration's Pediatric Advisory Committee is a primary source of the pediatric postmarketing safety review and has been associated with a number of labeling changes through its ongoing review process. Pediatric drug safety remains a critical part of the assessment of dose-effect relationship in the pediatric patient population during the drug development and postmarketing surveillance process.

Description of hypersensitivity adverse events following administration of heparin that was potentially contaminated with oversulfated chondroitin sulfate in early 2008.

PURPOSE: To characterize the nature of a heparin contaminant's clinical effects in cases reported to the Adverse Event Reporting System (AERS). The FDA received reports of heparin-associated adverse events (AEs) starting in late 2007-early 2008 during a national investigation of allergic-type events. The investigation identified Baxter Healthcare-brand heparin product due to its strongest association with the events. Later, oversulfated chondroitin sulfate (OSCS), a heparin-like contaminant, was discovered. METHODS: This study was a case series of heparin reports in AERS received 1 January 2008 to 31 March 2008. Variables considered were frequency of treatment settings, AEs, mortality; as well as heparin dose and OSCS contamination. RESULTS: Five hundred seventy-four AERS cases (unduplicated reports) were identified and included. Of 94 cases with a fatal outcome, 68 reported at least one AE term from the list used to identify an allergic-type event. Nearly 75% of AEs in cases of IV administration (n = 170/233) reportedly occurred within 10 minutes, whereas over half of subcutaneous administration cases (n = 13/23) resulted in times-to-event of greater than 24 hours. Although cases with a time-to-event of less than 10 minutes appeared to correlate with higher levels of OSCS contamination, no clear differences were noted between high- and low-to-absent OSCS concentration lots with respect to AEs observed. CONCLUSIONS: Intravenous administration and a higher OSCS concentration appeared to correlate with a more rapid onset of event. The FDA continues to monitor AEs associated with heparin use and has taken appropriate regulatory action to ensure a safe heparin drug supply.