Detection, Monitoring, and Mitigation of Drug-Induced Nephrotoxicity: A Pragmatic Approach.

The kidneys play a pivotal role in elimination of most drugs; therefore, a comprehensive understanding of renal physiology and pathology is important for those involved in drug development. High filtration capacity and metabolic activity make the kidneys vulnerable to drug-induced nephrotoxicity (DIN). Acute DIN may manifest on a background of renal impairment that has resulted from underlying disease, previously administered nephrotoxic medications, congenital renal abnormalities, or the natural aging process. The ability of the kidneys to compensate for DIN depends on the degree of pre-insult renal function. Therefore, it can be difficult to identify. The discovery and development of novel biomarkers that can diagnose kidney damage earlier and more accurately than current clinical measures and may be effective in detecting DIN. The goal of this manuscript is to provide a pragmatic and evidence-based supportive guidance for the early identification and management of DIN during the drug development process for clinical trial participants of all ages. The overall objective is to minimize the impact of DIN on kidney function and to collect renal safety data enabling risk analysis and mitigation.

Innovations in Pediatric Therapeutics Development: Principles for the Use of Bridging Biomarkers in Pediatric Extrapolation.

Even with recent substantive improvements in health care in pediatric populations, considerable need remains for additional safe and effective interventions for the prevention and treatment of diseases in children. The approval of prescription drugs and biological products for use in pediatric settings, as in adults, requires demonstration of substantial evidence of effectiveness and favorable benefit-to-risk. For diseases primarily affecting children, such evidence predominantly would be obtained in the pediatric setting. However, for conditions affecting both adults and children, pediatric extrapolation uses scientific evidence in adults to enable more efficiently obtaining a reliable evaluation of an intervention's effects in pediatric populations. Bridging biomarkers potentially have an integral role in pediatric extrapolation. In a setting where an intervention reliably has been established to be safe and effective in adults, and where there is substantive evidence that disease processes in pediatric and adult settings are biologically similar, a 'bridging biomarker' should satisfy three additional criteria: effects on the bridging biomarker should capture effects on the principal causal pathway through which the disease process meaningfully influences 'feels, functions, survives' measures; secondly, the experimental intervention should not have important unintended effects on 'feels, functions, survives' measures not captured by the bridging biomarker; and thirdly, in statistical analyses in adults, the intervention's net effect on 'feels, functions, survives' measures should be consistent with what would be predicted by its level of effect on the bridging biomarker. A validated bridging biomarker has considerable potential utility, since an intervention's efficacy could be extrapolated from adult to pediatric populations if evidence in children establishes the intervention not only to be safe but also to have substantive effects on that bridging biomarker. Proper use of bridging biomarkers could increase availability of reliably evaluated therapies approved for use in pediatric settings, enabling children and their caregivers to make informed choices about health care.

Inclusion of Adolescents in Adult Clinical Trials: Report of the Institute for Advanced Clinical Trials for Children's Pediatric Innovation Research Forum.

Including adolescents in adult clinical trials can play an important role in making innovative new medicines available to children in a timelier fashion. Stakeholders involved in the processes leading to regulatory approval and labeling of new drugs recognize that challenges exist in involving adolescents and older children in clinical trials before the safety and efficacy of these drugs are established for adults. However, it has been possible to design and execute phase 3 trials that combine adults with adolescents which are medically and scientifically sound and ethically justified. Based on this experience and considerations of the medical and scientific, ethical, and operation-related matters, the 2019 Pediatric Innovation Research Forum advocated for the position that adolescents routinely be considered for enrollment in phase 3 clinical trials. The Forum also concluded that exclusion of adolescents in adult pivotal trials occur only when a thorough evaluation of the target disease and the potential benefit and risks of the study intervention supports a delay in their involvement until after completion of clinical trials in adults.

Incorporating Innovative Techniques Toward Extrapolation and Efficient Pediatric Drug Development.

The conduct of pediatric clinical trials is legally required, monitored, and encouraged in major geographic areas such as the United States and Europe. However, because pediatric patients are considered vulnerable populations, they should only be enrolled as research subjects in a clinical trial if enrolling adult subjects will not be able to answer the scientific question related to the health and welfare of children. Thus, there is an ethical obligation to build the foundation for the use of pediatric extrapolation and related innovative analytical strategies with appropriately designed pediatric and adult clinical trials to reduce the amount of, or general need for, additional information needed from children to reach conclusions. This manuscript discusses innovative applications of clinical trial designs, analytic strategies to more efficiently leverage prior information, and modeling approaches that impact the data required to determine efficacy of an investigational drug in pediatrics. The planning of pediatric trials and regulatory interactions related to required pediatric studies and the expectations for innovative analytics are also discussed.

Enrollment of Neonates in More Than One Clinical Trial.

Because the highest rates of morbidity and mortality in neonates are seen in those born at <32 weeks' gestation, this group has the most urgent need for novel therapies to improve survival and outcome. Legislative efforts in the United States and Europe have attempted to address this issue by requiring the study of drugs, biological and nutritional products, devices, and other therapies in this population through a combination of high-quality regulatory and clinical trials, quality improvement initiatives, and observational studies. Because there are relatively small numbers of very preterm neonates born each year in any 1 country or continent, and because a significant number of clinical trials are recruiting at any 1 time, a neonate may meet enrollment criteria for >1 clinical trial. Neonatal units that have the infrastructure and resources to engage in research frequently face the question of whether it is permissible to enroll a neonate in >1 trial. This article examines the pertinent scientific, ethical, regulatory, and industry issues that should be taken into account when considering enrolling neonates in multiple clinical studies.

Safety, dosing, and pharmaceutical quality for studies that evaluate medicinal products (including biological products) in neonates.

The study of medications among pediatric patients has increased worldwide since 1997 in response to new legislation and regulations, but these studies have not yet adequately addressed the therapeutic needs of neonates. Additionally, extant guidance developed by regulatory agencies worldwide does not fully address the specificities of neonatal drug development, especially among extremely premature newborns who currently survive. Consequently, an international consortium from Canada, Europe, Japan, and the United States was organized by the Critical Path Institute to address the content of guidance. This group included neonatologists, neonatal nurses, parents, regulators, ethicists, clinical pharmacologists, specialists in pharmacokinetics, specialists in clinical trials and pediatricians working in the pharmaceutical industry. This group has developed a comprehensive, referenced White Paper to guide neonatal clinical trials of medicines - particularly early phase studies. Key points include: the need to base product development on neonatal physiology and pharmacology while making the most of knowledge acquired in other settings; the central role of families in research; and the value of the whole neonatal team in the design, implementation and interpretation of studies. This White Paper should facilitate successful clinical trials of medicines in neonates by informing regulators, sponsors, and the neonatal community of existing good practice.

Special article: 2014 Pediatric Clinical Trials Forum.

In November 2014, the American Academy of Pediatrics convened key stakeholders to discuss the feasibility of accelerating children's medical advances by creating an independent global Pediatric Clinical Trials Network. The Forum identified challenges posed by the U.S. and global clinical trial systems regarding testing and disseminating drugs and devices for pediatric patients. Stakeholders mapped a vision to improve the safety and efficacy of pediatric drugs, biological products, and medical devices by creating a global Pediatric Clinical Trials Network. Such a Network would act as a central infrastructure for pediatric subspecialties and enable dedicated staff to provide clinical research sites with scientific, medical, and operational support. A Network would facilitate development and availability of innovative, high-quality therapies to extend and enhance the lives of neonates, infants, children, adolescents, and young adults. Participants expressed strong interest in forming such a Network, since drugs and devices still come to market without adequate pediatric indications-particularly in neonatology and rare diseases. Participants developed a Consensus Statement expressing their shared vision for a Network: Attendees of the Pediatric Clinical Trials Stakeholder Forum resolved to establish a Global Pediatric Clinical Trials Network and are committed to engage in the work to create and sustain it.

Detection of early diastolic alterations by tissue Doppler imaging in untreated childhood-onset essential hypertension.

The aim of the study was to determine the presence of preclinical diastolic dysfunction in hypertensive children relative to normotensive children by Tissue Doppler Imaging (TDI). We prospectively enrolled children with untreated essential hypertension in absence of any other disease and a matched healthy control group with normal blood pressure (BP); both groups confirmed by clinic BP and a 24-hour ambulatory BP monitoring. Echocardiographic diastolic parameters were determined using spectral transmitral inflow Doppler, flow propagation velocity, TDI, and systolic parameters were determined via midwall shortening fraction and ejection fraction. A total of 80 multiethnic children were prospectively enrolled for the study: 46 hypertensive (median age, 13 years; 72% males) and 34 control (median age, 14 years; 65% males). The only echocardiography parameters that had a statistically significant change compared with the control children, were regional mitral Ea, Aa, and the E/Ea ratio by TDI. In comparison with controls, hypertensive children had lower Ea and Aa velocities of anterior and posterior walls and higher lateral wall E/Ea ratio. The decrease in posterior wall Ea and Aa remained significant after adjustment for gender, age, body mass index, ethnicity, and left ventricular hypertrophy on multivariate analysis. The lateral and septal wall E/Ea ratios correlated significantly with fasting serum insulin levels on similar multivariate analysis. Decreased regional TDI velocities were seen with preserved left ventricular systolic function even when other measures of diastolic dysfunction remained unchanged in untreated hypertensive children. Hypertension and serum insulin levels had strong associations with preclinical diastolic alterations in children.

Aortic dilatation in children with systemic hypertension.

The aim of the study was to determine the presence of aortic dilatation in hypertensive children, the prevalence of which is 4% to 10% in hypertensive adults. Prospectively enrolled multiethnic children, untreated for their hypertension, underwent an echocardiogram to exclude congenital heart disease and evaluate for end-organ damage and aortic size. The aorta was measured in the parasternal long-axis view at three levels: the sinus of Valsalva, supra-tubular junction, and the ascending aorta. Aortic dilatation was determined by z-score >2 at any one of the levels measured. Hypertension was defined as blood pressure above the 95th percentile based on the Fourth Working Group criteria confirmed by 24-hour ambulatory blood pressure monitoring. Among 142 consecutive hypertensive children (median age, 14 years; 45% females) aortic dilatation was detected in 2.8% (95% confidence interval, 1%-7%; median age, 16 years; 100% females). Children with aortic dilatation, when compared with those without, had significantly more aortic valve insufficiency (P = .005) and left ventricular hypertrophy (P = .018). Prevalence of aortic dilatation was 2.8% and was associated with significantly more aortic insufficiency and left ventricular hypertrophy in comparison to those without aortic dilatation.

Quantitative Extrapolation: An Approach to Validation of Adult Drug Efficacy in Pediatric Subjects.

Confirmation of efficacy in pediatric drug development has traditionally required large, fully powered efficacy studies that have proven to have major feasibility and ethical challenges. Extrapolation of efficacy in the framework provided by the US Food and Drug Administration and European Medicines Agency is an appropriate solution when there is similarity of disease. When there is uncertainty regarding the degree of disease similarity, partial extrapolation may be utilized. The authors propose a more quantitative approach to partial extrapolation (ie, quantitative extrapolation), involving (1) integration of adult pharmacokinetic (PK), pharmacodynamic (PD), and clinical outcome data using pharmacometric models, (2) extrapolation using the adult pharmacometric model to predict PD and efficacy outcomes in pediatric subjects, and (3) validation of pediatric predictions with a streamlined plan of pediatric trials (ie, a quantitative extrapolation plan). A case study is presented for quantitative extrapolation using dipeptidyl peptidase 4 (DPP-4) inhibitors. In this example, the authors demonstrate how adult PK, PD, and HbA1c data can be integrated using a pharmacometric model for DPP-4 inhibitors with pediatric dose selection and efficacy validated with relatively few pediatric subjects.

Evaluation of serum creatinine concentration-based glomerular filtration rate equations in pediatric patients with chronic kidney disease.

STUDY OBJECTIVE: To evaluate the accuracy of four equations based on serum creatinine concentration-the original Schwartz equation and the Leger, Bedside Chronic Kidney Disease in Children (CKiD), and Counahan-Barratt equations-for determining glomerular filtration rate (GFR) in pediatric patients with chronic kidney disease. DESIGN: Retrospective, observational, cross-sectional study. SETTING: Single-center, academic, outpatient pediatric nephrology clinic. PATIENTS: Fifty-three pediatric patients with stages 2-5 chronic kidney disease who completed GFR assessment with (125) I-iothalamate between January 2002 and January 2005. MEASUREMENT AND MAIN RESULTS: Data were collected from each patient's medical record. Glomerular filtration rate data were analyzed using 59 evaluations from the 53 pediatric patients. (125) I-iothalamate clearance was used as the index GFR. The Bedside CKiD and Counahan-Barratt equations outperformed the Schwartz and Leger equations when the index GFR was less than 60 ml/minute/1.73 m(2) ; the Schwartz and Counahan-Barratt equations performed best for index GFRs of 60 ml/minute/1.73 m(2) or greater. Overestimation was highest with the Schwartz and Leger equations (> 20% index GFR in 57.6% and 62.7% of patients, respectively). Underestimation was highest with the Bedside CKiD and Counahan-Barratt equations (> 20% index GFR in 30.5% and 28.8%, respectively). CONCLUSION: The new Bedside CKiD equation performed well for pediatric patients with moderate-to-severe chronic kidney disease, but less well for pediatric patients with mild disease. Additional studies are needed to develop more precise GFR equations using serum creatinine concentration.

Prevalence of persistent prehypertension in adolescents.

OBJECTIVE: To measure the prevalence of persistent prehypertension in adolescents. STUDY DESIGN: We collected demographic and anthropometric data and 4 oscillometric blood pressure (BP) measurements on 1020 students. The mean of the second, third, and fourth BP measurements determined each student's BP status per visit, with up to 3 total visits. Final BP status was classified as normal (BP <90th percentile and 120/80 mm Hg at the first visit), variable (BP ≥ 90th percentile or 120/80 mm Hg at the first visit and subsequently normal), abnormal (BP ≥ 90th percentile or 120/80 mm Hg at 3 visits but not hypertensive), or hypertensive (BP ≥ 95th percentile at 3 visits). The abnormal group included those with persistent prehypertension (BP ≥ 90th percentile or 120/80 mm Hg and <95th percentile on 3 visits). Statistical analysis allowed for comparison of groups and identification of characteristics associated with final BP classification. RESULTS: Of 1010 students analyzed, 71.1% were classified as normal, 15.0% as variable, 11.5% as abnormal, and 2.5% as hypertensive. The prevalence of persistent prehypertension was 4.0%. Obesity similarly affected the odds for variable BP (OR, 3.9; 95% CI, 2.5-6.0) and abnormal BP (OR, 3.4; 95% CI, 2.0-5.9), and dramatically increased the odds for hypertension (OR, 38.4; 95% CI, 9.4-156.6). CONCLUSION: Almost 30% of the students had at least one elevated BP measurement significantly influenced by obesity. Treating obesity may be essential to preventing prehypertension and/or hypertension.

Development of hypertension in adolescents with pre-hypertension.

OBJECTIVE: To evaluate the risk for developing incident hypertension (HTN) in adolescents with pre-hypertension. STUDY DESIGN: A secondary analysis of students participating in multiple school-based blood pressure (BP) screens from 2000 to 2007 was completed. At each screen, height, weight, and 2 to 4 BPs were measured on as many as 3 occasions when BP remained ≥ 95th percentile. Students with confirmed HTN at their initial screen were excluded, and incident HTN was defined as having a BP ≥ 95th percentile at all 3 visits of a later screen. Incidence rates (IR) and hazard ratios (HR) were calculated by using Cox Proportional models. RESULTS: Of 1006 students, HTN developed in 11 (IR 0.5%/year) in a mean of 2.1 years of observation. IRs were higher in "at-risk" students (pre-hypertensive or hypertensive with follow-up BP <95th percentile), 1.4%/year (HR, 4.89; 1.48-16.19) and students with a BP ≥ 90th percentile at 3 baseline visits, 6.6%/year HR 24.33 (5.68-104.29)]. Although not significant, students with pre-hypertension by the 2004 Task Force definition also had an increased IR of 1.1%/year (HR, 2.98; 0.77-11.56)]. CONCLUSION: Elevated BP increases the risk for the development of HTN during adolescence. Effective strategies for preventing HTN in at-risk adolescents are needed.