Did pediatric drug development advance epilepsy treatment in young patients? It is time for new research goals.

Modern drugs have changed epilepsy, which affects people of all ages. However, for young people with epilepsy, the framework of drug development has stalled. In the wake of the thalidomide catastrophe, the misconception emerged that for people < 18 years of age drugs, including antiseizure medications (ASMs), need separate proof of efficacy and safety, overall called "pediatric drug development". For ASMs, this has changed to some degree. Authorities now accept that ASMs are effective in < 18 years as well, but they still require "extrapolation of efficacy," as if minors were another species. As a result, some of the pediatric clinical epilepsy research over the past decades was unnecessary. Even more importantly, this has hampered research on meaningful research goals. We do not need to confirm that ASMs work before as they do after the 18th birthday. Instead, we need to learn how to prevent brain damage in young patients by preventing seizures and optimize ASMs' uses. Herein we discuss how to proceed in this endeavor.

"Pediatric" Drug Studies Might Be the Largest Abuse in Medical Research in History. It Is Time for Lawyers to Step In.

A new type of research has emerged with United States and European Union pediatric laws that request/demand separate clinical studies for vaccines and drugs in minors less than 18 years of age. Physiologically, minors mature before their 18th birthday. Medicine treats the body, not the administrative status. Many "pediatric" studies are performed in minors that bodily are no longer children, which makes them pointless. Traditional malpractice litigation in clinical research involves patients that were harmed in clinical studies. In the new type of "pediatric" studies, drugs known to work in humans are retested, pretending that "children" are uniquely different, which is incorrect. Minors are not another species. Patients are not treated at all (placebo group) or below standard-of-care (comparison to outdated treatment). Pediatric laws are the law, but not a free pass for harming patients. Where "pediatric" studies violate accepted norms of medical practice, lawyers should be aware of this challenge at the interface of medicine and law.

Neurology's vital role in preventing unnecessary and potentially harmful pediatric studies.

INTRODUCTION: Regulatory authorities recognize two human populations: adults and children defined as <18 years. For drug approval, they demand separate studies. But humans mature slowly during puberty. The 18th birthday is an administrative limit that does not correspond to a physiological change. Separate drug approval before/after the 18th birthday reflects the children-are-therapeutic-orphans concept that emerged after 1962. The Food and Drug Administration (FDA) has backed away from this concept for antiepileptic drugs, but sticks to it in other areas. In contrast, the European Medicines Agency (EMA) is continuously expanding its demand for 'pediatric' studies. Parents hesitate increasingly to let their children participate in questionable studies. AREAS COVERED: Neurologists challenge the children-are-therapeutic-orphans mantra. Young patients do not need separate proof of efficacy & safety, but appropriate dosing recommendations. Minors should be treated as human beings, instead of being abused in questionable studies. EXPERT OPINION: Young patients with multiple sclerosis and other neurological diseases deserve studies with therapeutic intentions. 'Pediatric' careers have emerged in academia, regulatory authorities, and pharmaceutical companies. Institutional Review Boards/ Ethics Committees should suspend questionable 'pediatric' studies and reject newly submitted ones. The medical professions should distance themselves from questionable 'pediatric' research that reflects massive conflicts of interest.

COVID-19 and Treatment and Immunization of Children-The Time to Redefine Pediatric Age Groups is Here.

Children are infected with coronavirus disease 2019 (COVID-19) as often as adults, but with fewer symptoms. During the first wave of the COVID-19 pandemic, multisystem inflammatory syndrome (MIS) in children (MIS-C), with symptoms similar to Kawasaki syndrome, was described in young minors testing positive for COVID-19. The United States (US) Centers for Disease Control and Prevention (CDC) defined MIS-C as occurring in <21-year-olds, triggering hundreds of PubMed-listed papers. However, postpubertal adolescents are no longer children biologically; the term MIS-C is misleading. Furthermore, MIS also occurs in adults, termed MIS-A by the CDC. Acute and delayed inflammations can be triggered by COVID-19. The 18th birthday is an administrative not a biological age limit, whereas the body matures slowly during puberty. This blur in defining children leads to confusion regarding MIS-C/MIS-A. United States and European Union (EU) drug approval is handled separately for children, defined as <18-year-olds, ascribing non-existent physical characteristics up to the 18th birthday. This blur between the administrative and the physiological meanings for the term child is causing flawed demands for pediatric studies in all drugs and vaccines, including those against COVID-19. Effective treatment of all conditions, including COVID-19, should be based on actual physiological need. Now, the flawed definition for children in the development of drugs and vaccines and their approval is negatively impacting prevention and treatment of COVID-19 in minors. This review reveals the necessity for redefining pediatric age groups to rapidly establish recommendations for optimal prevention and treatment in minors.

Patterns of Hepatitis C-Related Inpatient Mortality in the United States in the Era of Direct-Acting Antivirals.

BACKGROUND & AIMS: Direct-acting antivirals (DAA) have revolutionized the management of hepatitis C virus (HCV) infection. Data on national inpatient mortality in this new era are scarce. This study aimed to evaluate inpatient mortality among HCV-related hospital stays in the United States (US) during the years DAA were available. METHODS: We conducted a cross-sectional analysis of the National Inpatient Sample (NIS) between 2012 and 2016. Using discharge weights, national estimates of HCV-related hospitalizations were calculated. Simple and multiple logistic regressions were performed to identify factors associated with inpatient mortality. RESULTS: A total of 67,630 hospitalizations from NIS were HCV-related, accounting for an estimated 338,150 hospitalizations during 2012 - 2016. These hospitalizations have estimated average annual total charges of $4.6 billion, adjusted to 2020 US dollars. The rate of inpatient mortality declined modestly from 5.25% in 2012 to 4.75% in 2016 (P=0.07). Over the 5-year study period, the proportion of in-hospital deaths increased for black patients, Medicaid beneficiaries, and patients with substance-related disorders. Controlling for known predictors, the odds of inpatient mortality were significantly greater among black patients compared to white patients (OR= 1.27 [95% CI=1.16 - 1.39]). CONCLUSIONS: The burden of HCV infection is substantial given the disease is now curable. Our findings indicate that major disparities in the HCV disease burden exist in the era of DAA.

Pharmacogenomics and Opioid Use Disorder: Clinical Decision Support in an African American Cohort.

Opioid use disorder (OUD) constitutes a significant public health burden as opioid overdose deaths have continued to rise in the United States. Although treatment modalities are available to manage OUD, some patients experience challenges achieving their OUD management goals. Some of these challenges may be attributable to inherited genetic variations, or polymorphisms, on the genes that code for proteins impacting the pharmacokinetics or pharmacodynamics of medications used in OUD management. Clinical pharmacogenomics testing can elucidate these polymorphisms; however, a lack of real-world evidence for the use of pharmacogenomics in OUD management complicates the implementation process. We conducted a retrospective cohort study of 113 patients undergoing buprenorphine-based OUD management in Northeast Washington D.C. to determine if clinical pharmacogenomics testing for CYP3A4 and CYP3A5 would impact treatment outcomes. Data were collected from the electronic medical record (EMR) from December 30, 2015 to December 31, 2016. Study outcomes were based on presence of withdrawal symptoms, instances of unauthorized substances in urine drug tests (UDTs), and sublingual buprenorphine/naloxone (SBN) dose with standard-of-care (SOC) dosing versus pharmacogenomics (PGx)-based dosing. Pearson correlation tests, Wilcoxon signed rank tests, Wilcoxon rank sum tests, and one-way ANOVA tests were used. Linear and logistic regression analyses were used to assess predictors of withdrawal symptomatology. Kaplan-Meier survival analyses were used to assess time to first withdrawal. Our research suggests that patients with at least one copy of the CYP3A4*1B allele exhibit an accelerated rate of metabolism compared to the wild-type allele CYP3A4*1.

Factors Associated with Prescribing Broad-Spectrum Antibiotics for Children with Upper Respiratory Tract Infections in Ambulatory Care Settings.

OBJECTIVES: Broad-spectrum antibiotics are frequently prescribed for children with upper respiratory tract infections (URI). Excessive use of broad-spectrum antibiotics leads to the emergence of resistant bacteria. This study aimed to identify factors associated with prescribing broad-spectrum antibiotics among children younger than 18 years presenting with URI in outpatient settings. METHODS: We conducted a cross-sectional analysis of the National Ambulatory Medical Care Survey (NAMCS) and the National Hospital Ambulatory Medical Care Survey-Outpatient Departments (NHAMCS-OPD) between 2006 and 2010. Descriptive statistics of visits from children with URI were estimated. Simple and multiple logistic regression analyses were used to identify socio-demographic and clinical characteristics associated with broad-spectrum antibiotic prescribing. We also completed a stratified analysis by age (⩽2 vs >2). RESULTS: A total of 4013 outpatient visits for children with URI from both NAMCS and NHAMCS-0PD data were examined. Broad-spectrum antibiotics were prescribed in 39% of the visits, accounting for an estimated 6.8 million visits annually. Multivariable analysis showed that visits in the South region (odds ratio [OR] = 2.38; 95% confidence interval [CI]: 1.38-4.10) compared with the West region and visits with diagnoses of acute sinusitis (OR = 2.77; 95% CI: 1.65-4.63) and acute otitis media (OR = 1.90; 95% CI: 1.32-2.74) compared with those with acute pharyngitis were associated with greater odds of broad-spectrum antibiotic prescribing. CONCLUSIONS: The prescribing of broad-spectrum antibiotics is common for children with URI in ambulatory care settings. Diagnosis and management of URI remain a critical area for awareness campaigns promoting judicious use of antibiotics.

Patient perceptions of a pharmacy star rating model.

OBJECTIVES: To identify patients' understanding of what constitutes a "quality pharmacy" and to obtain their feedback regarding the development and use of the pharmacy star rating model, a pharmacy-specific aggregate performance score based on the Centers for Medicare and Medicaid Services' Medicare Star Rating. DESIGN: Prospective cross-sectional study. SETTING AND PARTICIPANTS: Focus groups were conducted in Arizona, California, Mississippi, Maryland, and the District of Columbia, and one-on-one interviews were conducted in Indiana. Eligible patients were required to routinely use a community pharmacy. MAIN OUTCOME MEASURES: Consumer insights on their experiences with their pharmacies and their input on the pharmacy star rating model were attained. Key themes from the focus groups and interviews were obtained through the use of qualitative data analyses. RESULTS: Forty-nine subjects from 5 states and DC participated in 6 focus groups and 4 one-on-one interviews. Eighty-eight percent of participants reported currently taking at least 1 medication, and 87% reported having at least 1 health condition. The 7 themes identified during qualitative analysis included patient care, relational factors for choosing a pharmacy, physical factors for choosing a pharmacy, factors related to use of the pharmacy star rating model, reliability of the pharmacy star rating model, trust in pharmacists, and measures of pharmacy quality. Most participants agreed that the ratings would be useful and could aid in selecting a pharmacy, especially if they were moving to a new place or if they were dissatisfied with their current pharmacy. CONCLUSION: Pharmacy quality measures are new to patients. Therefore, training and education will need to be provided to patients, as pharmacies begin to offer additional clinical services, such as medication therapy management and diabetes education. The use of the pharmacy star rating model was dependent on the participants' situation when choosing a pharmacy.

Pharmacogenomics-guided policy in opioid use disorder (OUD) management: An ethnically-diverse case-based approach.

INTRODUCTION: Opioid use disorder (OUD) is characterized by a problematic pattern of opioid use leading to clinically-significant impairment or distress. Opioid agonist treatment is an integral component of OUD management, and buprenorphine is often utilized in OUD management due to strong clinical evidence for efficacy. However, interindividual genetic differences in buprenorphine metabolism may result in variable treatment response, leaving some patients undertreated and at increased risk for relapse. Clinical pharmacogenomics studies the effect that inherited genetic variations have on drug response. Our objective is to demonstrate the impact of pharmacogenetic testing on OUD management outcomes. METHODS: We analyzed a patient who reported discomfort at daily buprenorphine dose of 24 mg, which was a mandated daily maximum by the pharmacy benefits manager. Regular urine screenings were conducted to detect the presence of unauthorized substances, and pharmacogenetic testing was used to determine the appropriate dose of buprenorphine for OUD management. RESULTS: At the 24 mg buprenorphine daily dose, the patient had multiple relapses with unauthorized substances. Pharmacogenetic testing revealed that the patient exhibited a cytochrome P450 3A4 ultrarapid metabolizer phenotype, which necessitated a higher than recommended daily dose of buprenorphine (32 mg) for adequate OUD management. The patient exhibited a reduction in the number of relapses on the pharmacogenetic-based dose recommendation compared to standard dosing. CONCLUSION: Pharmacogenomic testing as clinical decision support helped to individualize OUD management. Collaboration by key stakeholders is essential to establishing pharmacogenetic testing as standard of care in OUD management.

An evaluation of hepatitis C knowledge and correlations with health belief model constructs among African American "baby boomers".

BACKGROUND: Baby boomers (people born between 1945 and 1965) are responsible for three-quarters of Hepatitis C (HCV) infections in the US; however, HCV testing is distinctly underused by them. AIM: To assess the status, predictors, and correlates of HCV knowledge among African-American baby boomers (AABBs) in Washington, DC. METHODS: A cross-sectional survey among persons aged 46-69 was conducted using audio computer-assisted self-interviewing (ACASI). Data on HCV knowledge, socio-demographics, prior history of HCV testing, health-related characteristics, HCV vulnerability and HCV treatment perceptions were collected. Descriptive statistics was used to describe the study population. Pearson correlations were used to examine linear associations between HCV knowledge and Health Belief Model constructs related to HCV. Linear regression analysis was conducted to assess the predictors of knowledge. RESULTS: Out of the 137 participants, about sixty percent (60.6%) were females, mean age 59±6.40; 44.8% had at least a college education. The average knowledge score was low (48.7%). HCV knowledge was significantly correlated with constructs of perceived severity and perceived benefits. Age (ß=-0.10; p=0.003), and level of education (ß=0.93, p=0.027) were significant predictors. CONCLUSIONS: Overall, respondents have a low level of knowledge. The lower level of education and older age were significant predictors of inadequate HCV knowledge. Thus, HCV education among these people may be a vital component in reducing the gaps in HCV knowledge.