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, 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.

Apixaban or enoxaparin for thromboprophylaxis after knee replacement.

BACKGROUND: The optimal strategy for thromboprophylaxis after major joint replacement has not been established. Low-molecular-weight heparins such as enoxaparin predominantly target factor Xa but to some extent also inhibit thrombin. Apixaban, a specific factor Xa inhibitor, may provide effective thromboprophylaxis with a low risk of bleeding and improved ease of use. METHODS: In a double-blind, double-dummy study, we randomly assigned patients undergoing total knee replacement to receive 2.5 mg of apixaban orally twice daily or 30 mg of enoxaparin subcutaneously every 12 hours. Both medications were started 12 to 24 hours after surgery and continued for 10 to 14 days. Bilateral venography was then performed. The primary efficacy outcome was a composite of asymptomatic and symptomatic deep-vein thrombosis, nonfatal pulmonary embolism, and death from any cause during treatment. Patients were followed for 60 days after anticoagulation therapy was stopped. RESULTS: A total of 3195 patients underwent randomization, with 1599 assigned to the apixaban group and 1596 to the enoxaparin group; 908 subjects were not eligible for the efficacy analysis. The overall rate of primary events was much lower than anticipated. The rate of the primary efficacy outcome was 9.0% with apixaban as compared with 8.8% with enoxaparin (relative risk, 1.02; 95% confidence interval, 0.78 to 1.32). The composite incidence of major bleeding and clinically relevant nonmajor bleeding was 2.9% with apixaban and 4.3% with enoxaparin (P=0.03). CONCLUSIONS: As compared with enoxaparin for efficacy of thromboprophylaxis after knee replacement, apixaban did not meet the prespecified statistical criteria for noninferiority, but its use was associated with lower rates of clinically relevant bleeding and it had a similar adverse-event profile. (ClinicalTrials.gov number, NCT00371683.)

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.

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.

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.

The efficacy and safety of the novel aldosterone antagonist eplerenone in children with hypertension: a randomized, double-blind, dose-response study.

OBJECTIVES: To determine the efficacy and safety of eplerenone therapy in children with hypertension. STUDY DESIGN: A total of 304 children age 4-16 years with systolic blood pressure (SBP) >or=95th percentile were randomized to low-dose (25 mg daily), middle-dose (25 mg twice daily), or high-dose (50 mg twice daily) eplerenone (phase A), then rerandomized to active therapy or placebo for another 4 weeks (phase B). The primary endpoint was change in SBP in phase B. RESULTS: During phase A, mean SBP decreased from baseline by 8 mm Hg, and diastolic blood pressure (DBP) decreased by up to 3.8 mm Hg; no dose-response relationship was demonstrated. Mean differences in SBP from placebo during phase B were -2.61 for the low-dose group, +2.32 for the middle-dose group, and -2.76 mm Hg for the high-dose group; only the reduction in the high-dose group was statistically significant (P = .048). No significant effects on DBP of eplerenone therapy relative to placebo were detected. Eplerenone was well tolerated, with a rate of adverse events comparable to that of placebo. CONCLUSIONS: Short-term treatment with eplerenone reduced blood pressure in children with hypertension and had acceptable tolerability.

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.

Prevalence of hypertension and pre-hypertension among adolescents.

OBJECTIVE: To determine the prevalence of hypertension and pre-hypertension on the basis of the 2004 National High Blood Pressure Education Program Working Group guidelines in an adolescent school-screening population. STUDY DESIGN: Cross-sectional assessment of blood pressure (BP) in 6790 adolescents (11-17 years) in Houston schools was conducted from 2003 to 2005. Initial measurements included height, weight, and 4 oscillometric BP readings. Repeat measurements were obtained on 2 subsequent occasions in students with persistently elevated BP. Final prevalence was adjusted for loss to follow-up and logistic regression used to assess risk factors. RESULTS: BP distribution at initial screen was 81.1% normal, 9.5% pre-hypertension, and 9.4% hypertension (8.4% Stage 1; 1% Stage 2). Prevalence after 3 screenings was 81.1% normal, 15.7% pre-hypertension, and 3.2% hypertension (2.6% Stage 1; 0.6% Stage 2). Hypertension and pre-hypertension increased with increasing body mass index. Sex, race, and classification as either at-risk for overweight or overweight were independently associated with pre-hypertension. Only classification as overweight was associated with hypertension. CONCLUSIONS: Application of new classification guidelines for adolescents with elevated BP reveals approximately 20% are at risk for hypertension. Further research determining the significance of each BP category and refining definitions to account for BP variability is warranted.

Efficacy and safety of extended release metoprolol succinate in hypertensive children 6 to 16 years of age: a clinical trial experience.

OBJECTIVE: To evaluate the efficacy, tolerability, and blood pressure (BP) lowering effect of extended release metoprolol succinate (ER metoprolol) in children 6 to 16 years of age with established hypertension. STUDY DESIGN: Patients were randomized to one of four treatment arms: placebo or ER metoprolol (0.2 mg/kg, 1.0 mg/kg, or 2.0 mg/kg). Data were analyzed on 140 intent-to-treat patients. RESULTS: Mean age (+/-SD) was 12.5 +/- 2.8 years and mean baseline BP was 132/78 +/- 9/9 mmHg. Following 4 weeks of treatment, mean changes in sitting BP were: placebo = -1.9/-2.1 mmHg; ER metoprolol 0.2 mg/kg = -5.2/-3.1 mmHg; 1.0 mg/kg = -7.7/-4.9 mmHg; 2.0 mg/kg = -6.3/-7.5 mmHg. Compared with placebo, ER metoprolol significantly reduced systolic blood pressure (SBP) at the 1.0 and 2.0 mg/kg dose (P = .027 and P = .049, respectively), reduced diastolic blood pressure (DBP) at the 2.0 mg/kg dose (P = .017), and showed a statistically significant dose response relationship for the placebo-corrected change in DBP from baseline. There were no serious adverse events or adverse events requiring study drug discontinuation among patients receiving active therapy. CONCLUSION: These data indicate that ER metoprolol is an effective and well-tolerated treatment for hypertension in children.

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.

Racial differences are seen in blood pressure response to fosinopril in hypertensive children.

BACKGROUND: Few antihypertensive therapies have been systematically studied in children and dosages for many agents are either extrapolated from adult studies or obtained from small homogenous pediatric populations. It is well established that adult patients of different races show disparate response to angiotensin-converting enzyme (ACE) inhibitors, however no such studies have been performed in children. METHODS: Two hundred fifty three children ages 6-16 with hypertension or with high normal blood pressure with an associated medical condition requiring antihypertensive therapy were enrolled at 78 clinical sites in the US, Russia, and Israel in a double blind study to evaluate the efficacy of fosinopril compared to placebo. RESULTS: The racial composition of the cohort included 60.1% white (152/253), 20.6% black (52/253), 13.8% Hispanic (35/253), 2.0% Asian (5/253), 0.4% Native American (1/253), and 3.2% (8/253) children classified as other or of mixed race. After adjusting for baseline blood pressure and body surface area (BSA) there was no significant dose response seen in non-black patients. Non-blacks randomized to the low, medium, and high dosages of fosinopril all had a mean decrease of 12 mm Hg in their sequential systolic BP (SBP). Blacks, however, demonstrated a significant dose response to fosinopril; those who received the low dosage had a 5 mm Hg decrease in SBP, and those who received the high dosage had a mean 13 mm Hg decrease in SBP. CONCLUSIONS: Fosinopril was effective in treating hypertension, but black children required a higher dose per body weight in order to achieve adequate control. This suggests that black children treated with fosinopril for hypertension on average require higher doses to achieve adequate systolic blood pressure control that non-black children.

Population pharmacokinetics of amlodipine in hypertensive children and adolescents.

A population pharmacokinetic study was conducted in 74 hypertensive children (mean age 10.4 +/- 4.4 years [mean +/- SD]) receiving amlodipine (mean dose 0.17 +/- 0.13 mg/kg/d) chronically. Multiple blood samples were obtained from each subject to characterize amlodipine pharmacokinetics. Plasma amlodipine concentrations were determined by liquid chromatography/mass spectrophotometry with multiple-reaction monitoring detection. Population pharmacokinetic analysis was performed using NONMEM. Amlodipine concentrations were similar in subjects dosed either once or twice daily. Amlodipine pharmacokinetics were well described by a 1-compartment model with first-order absorption and elimination. For a subject at the population median weight (45 kg), predicted apparent clearances (CL/F) were 23.7 L/h for males and 17.6 L/h for females, and the apparent volume of distribution (V/F) was 25.1 L/kg. Dosing frequency did not appear to affect amlodipine concentrations in children. Weight-adjusted CL/F and V/F of amlodipine in younger children were significantly greater than in older children, suggesting a need for higher doses when treating young children with amlodipine.

Circadian pattern of blood pressure, heart rate, and double product in liver glycogen storage disease.

The objective of this study was to determine systolic, diastolic, and mean arterial blood pressure (SBP, DBP, and MAP), heart rate (HR), double-product (DP: SBP x HR), and activity levels and their 24h pattern in liver glycogen storage disease (LGSD) patients. A case series of 12 (11 pediatric and one adult) diurnally active LGSD (seven type I, three type III, and two type IX) subjects were simultaneously assessed by 24h ambulatory blood pressure monitoring and wrist actigraphy. Nine subjects were judged to be hypertensive based on the criterion of an elevated 24h mean SBP and/or DBP being elevated beyond reference standards or the SBP and/or DBP load (percentage of time BP exceeds normal values) being greater than 25%. Two of the three other subjects, not viewed as hypertensive based on their 24h average SBP or DBP, exhibited daytime or nighttime SBP and/or DBP load hypertension. Each study variables displayed statistically significant (p < 0.001) group circadian rhythmicity. The SBP, DBP, and MAP displayed comparable 24h patterns of appreciable amplitude (total peak-trough variation equal to 17.7, 23.6, and 19.6%, respectively, of the 24h mean) with highest values (orthophase) occurring approximately 11 h after the commencement of daytime activity. The sleep-time trough (bathyphase) occurred approximately 4.5 h before morning awakening. The statistically significant (p < 0.006) circadian rhythms of HR (amplitude equal to 33.2% of the 24h mean) and DP (amplitude equal to 49.4% of the 24h mean) peaked earlier, approximately 7.4 h into the daytime activity span. The sleep-time trough occurred approximately 3 h before morning awakening. The 24h pattern in the cardiovascular variables was correlated with the 24h pattern of activity, with r ranging from 0.50 for DBP to 0.39 for HR.

Measurement and treatment of elevated blood pressure in the pediatric patient with chronic kidney disease.

Hypertension, as in adults, is a frequent complication found in children with chronic kidney disease (CKD). Indeed, hypertension has now become one of the most prevalent chronic diseases of childhood. The most recent data available (2003) indicate that at least 38% of children with CKD in the United States are receiving antihypertensive therapy. Only recently has it been shown in children that hypertension, traditionally considered a marker for disease severity in children, is additionally a significant and independent risk factor for accelerated deterioration of kidney function and progression of CKD and a significant risk factor for cardiovascular disease. The following review outlines the differences and similarities of childhood versus adult hypertension with respect to measurement, diagnosis, treatment, and consequence in CKD. The definition of hypertension changes continually as a child grows with or without CKD. Despite numerous guidelines, the diagnosis of childhood hypertension continues to be based on epidemiologic data rather than evidence. For children, the current definition includes 2 categories: high normal, which is blood pressure (BP) between the 90th and 95th percentile, and hypertensive, which is BP above the 95th percentile. The evaluation of all hypertensive children should include a complete assessment of end-organ damage, including eyes, cardiovascular system (including blood vessels), kidneys, and nervous system. For children with CKD and end-stage renal disease (ESRD), a high percentage have left ventricular hypertrophy (LVH). The finding of end-organ damage or comorbidity (CKD, diabetes) in any child is an absolute indication for immediate pharmacologic therapy, whereas the presence of hypertension above the 95th percentile in children without CKD warrants initial intervention such as life style modification. The guidelines for measurement of BP in children with CKD are similar to those in children without CKD and include casual BP measurement, self-measured BP, and ambulatory BP monitoring. The recommendation for BP measurement in children is, when permitted, by auscultative method with a well-calibrated mercury manometer. Most casual BP measurements are performed with an automated oscillometric device whose validation has not been confirmed in children with CKD. The ambulatory BP monitor (ABPM) has 2 advantages: it significantly correlates with the presence of end-organ damage, and it identifies abnormal BP patterns that are frequently present in CKD patients, such as hypertension during the sleep period. An abnormal ABPM pattern can also be predictive of the development of end-organ damage. Treatment of hypertension in children, with and without CKD, is based on 3 factors: degree of BP elevation, the presence of cardiovascular risk factors, and the presence of end-organ damage. Additionally, the initial antihypertensive agent may be selected on available and age-appropriate formulations (eg, suspension and dosage selection). A physician treating a hypertensive child with CKD faces multiple challenges. They include selecting the convenience of available automated devices and the ABPM versus traditional auscultatory techniques upon which all normative standards have been based. Current research initiatives propose to develop pharmacokinetic and pharmacodynamics properties of antihypertensive medications and to study the effect of early intervention on end-organ damage.