Best Pharmaceuticals For Children Act Research Articles

Assessment of the Impact of Mandated Postmarketing Pediatric-Focused Safety Reviews on Safety-Related Regulatory Actions 2013-2019.

The US Food and Drug Administration's (FDA's) routine postmarketing drug safety monitoring may lead to safety-related labeling changes for identified risks. Additionally, the Best Pharmaceuticals for Children Act (BPCA) and Pediatric Research Equity Act (PREA) require the FDA to conduct postmarket pediatric-focused safety reviews of adverse events. The purpose of these pediatric reviews is to identify risks associated with drug or biological products 18 months after the FDA approves a pediatric labeling change pursuant to studies conducted under the BPCA or PREA. These reviews are presented to the FDA Pediatric Advisory Committee (PAC) or publicly posted on FDA's website. The aim of this study was to evaluate the impact of pediatric reviews prompted by BPCA/PREA from October 1, 2013, to September 30, 2019. The impact was quantified by the number of new safety signals identified and the subsequent safety-related labeling changes resulting from pediatric reviews relative to safety-related labeling changes triggered by other data sources. Among 163 products with at least one pediatric review completed, a new safety signal that resulted in a safety-related labeling change was found for 5 of these products (representing 3 active ingredients); none described risks specific to the pediatric population. Between October 2013 and September 2021, there were 585 safety-related labeling changes implemented for products with at least one completed pediatric review. Less than 1% of 585 safety-related labeling changes were the result of a mandated pediatric review. Our study suggests that mandated pediatric reviews conducted 18 months after a pediatric labeling change provided minimal value over other postmarket safety surveillance activities.

Improving Drug Therapy for Pediatric Patients: Unfinished History of Pediatric Drug Development.

Improving Drug Therapy for Pediatric Patients: Unfinished History of Pediatric Drug Development.

The Pediatric Pharmacy Association and Members Threaded Through a Career and the Impact on Pediatric Drug Development.

The Pediatric Pharmacy Association and Members Threaded Through a Career and the Impact on Pediatric Drug Development.

Formulation Challenges and Strategies to Develop Pediatric Dosage Forms.

The development of pediatric-specific dose forms is particularly difficult due to a variety of factors relating to pediatric population differences from adult populations. The buccal dosage form is considered a good alternative to oral dosage form if the latter cannot be used in pediatric patients. Both oral and buccal dosage formulations uphold great application qualities for pediatric patients. This review sheds light on both oral and buccal, as they are the most convenient dosage forms for pediatrics. The use of adult drugs to treat children is a legislation concern, as it may result in incorrect dose, safety, and efficacy. The Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) are two key pieces of legislation that encourage and regulate pediatric medication research. Both contribute to a well-balanced approach to emphasizing critical safety and efficacy warnings for the of medications within pediatric populations. These contributions are what enable companies to continue making significant investments in pediatric drug developments. Despite the importance of investigating medicines for children, there is still a demand for pediatric-specific formulations and dosage forms. Many formulations and dosage forms can be designed, among which the buccal drug delivery seems a good modality for pediatric-friendly dosage forms. The main issues associated with these pediatric dosage forms development, particularly clinical and physiological factors, are discussed in this review. In addition, formulation developments and regulatory expectations are highlighted. In turn, suggestions are made to potentially improve future pediatric formulation development.

Racial and Ethnic Diversity in Studies Funded Under the Best Pharmaceuticals for Children Act.

The Best Pharmaceuticals for Children Act (BPCA) incentivizes the study of on-patent medicines in children and mandates that the National Institutes of Health sponsor research on off-patent drugs important to pediatric therapeutics. Failing to enroll cohorts that reflect the pediatric population at large restricts the generalizability of such studies. In this investigation, we evaluate racial and ethnic minority representation among participants enrolled in BPCA-sponsored studies. Data were obtained for all participants enrolled in 33 federally funded studies of drugs and devices conducted from 2008 through June 2020. Observed racial and ethnic distributions were compared with expected distributions by sampling Census data at the same geographic frequency as in the studies. Racial and ethnic enrollment was examined by demography, geography, study type, study burden, and expected bias. Standard descriptive statistics, χ2, generalized linear models, and linear regression were applied. A total of 10 918 participants (51% male, 6.6 ± 8.2 years) were enrolled across 46 US states and 4 countries. Studies ranged from treatment outcome reviews to randomized, placebo-controlled trials. Minority enrollment was comparable to, or higher than, expected (+0.1% to +2.6%) for all groups except Asian Americans (-3.7%, P < .001). American Indian and Alaskan Native and multiracial enrollment significantly increased over the evaluation period (P < .01). There were no significant differences in racial distribution as a function of age or sex, although differences were observed on the basis of geography, study type, and study burden. This study revealed no evidence of racial and ethnic bias in enrollment for pediatric studies conducted with funding from BPCA, fulfilling the legislation's expectation to ensure adequate representation of all children.

Advocating for Minority Inclusion in Clinical Trials: A Call for Representation and Justice.

Off-label prescribing of medications has been a long-standing practice in pediatric medicine because, in the types of studies regarding safety, efficacy, and pharmacokinetics needed for labeling, researchers often only enroll adult subjects.1 The Best Pharmaceuticals for Children Act (BPCA) and Pediatric Research Equity Act have significantly increased the number of pediatric trials submitted to the US Food and Drug Administration for drug labeling in the past 10 years.1,2 Prioritizing minority enrollment in BPCA-funded clinical trials will increase the generalizability of scientific findings within the broader pediatric population.3In this issue of Pediatrics, Abdel-Rahman et al4 present new findings on the representation of racial and ethnic minorities participating in federally BPCA-funded pediatric studies. Pediatric enrollment in BPCA-funded studies remained comparable to or higher than expected in all minority groups, except Asian Americans. Despite observing some racial and ethnic differences in enrollment on the basis of geography, study type, and degree of study burden, in the findings from this report, it is suggested that overall, in BPCA-sponsored pediatric studies, there are no racial or ethnic biases or disparities in subject enrollment. However, as the authors note, we suspect that these studies were likely not sufficiently powered to reveal such differences between racial and ethnic groups, especially given the inherent incomplete capture of information on race and ethnicity. Although race and ethnicity are social constructs and crude proxies to account for the substantial heterogeneity of mixed ancestry, in their continued use in clinical trials, researchers have attempted to create standard terminology, and, in many historical studies, researchers have found clinically significant differences in pharmacokinetics and pharmacodynamics on the basis of these measures.5Historically, Black and Hispanic subjects are underrepresented in clinical trials.6 Lack of representation hinders our ability to discern factors that may influence a drug’s performance on the basis genetic ancestry and excludes the presence of particular racial and ethnic groups from inclusion within the full scientific body of evidence.7 Well-known barriers to subject enrollment in clinical trials include language preference, health literacy, geography, transportation, cost, and resources.8 In addition, the willingness of racial and ethnic minorities to participate in clinical trials has been significantly compromised by mistrust, historical abuses, and religious or cultural differences.9 Both concepts are further challenged in the pediatric population because of the ethical, clinical, and logistic considerations unique to children.10Although the current findings on BPCA-sponsored studies are encouraging, equitable demographic distribution of subjects enrolled in clinical trials should reflect our minimum standards of scientific rigor.11 In the adult literature, researchers discuss how stark underrepresentation of racial and ethnic minorities has limited access to potentially life-sustaining cancer drug treatments for eligible subjects at an increased risk for disease.12 In addition, drug therapies for adults with cardiac failure have been shown to perform differently on the basis of race and ethnicity.13 Therefore, the inclusion of racial and ethnic minorities in clinical trials should be free of bias and remains an issue of equity and justice.14 We suspect that there may be similar racial and ethnic differences in the performance of certain medications in pediatric populations; however, current trials may be underpowered to detect these differences. On the basis of findings from adult trials, developing strategies to increase and maintain minority inclusion in pediatric clinical trials remains imperative.Consideration of minority inclusion and subject enrollment should be tackled at the onset of clinical trial design and should include ensuring diversified BPCA site selection. Equitable demographic distribution of participants should be prioritized in such a way that a study is powered to reveal racial and ethnic differences. Furthermore, underscoring diversity and representation within the local study personnel is critical for both patient-oriented design and outreach. Finally, emphasizing the need for diversity and inclusion through community outreach and engagement regarding clinical trial participation is a key component to robust enrollment.The lack of racial and ethnic bias in patient enrollment in BPCA-funded sites is a positive sign, but historical evidence beckons caution. The call for diversity, equity, and inclusion remains vital to ensure that such findings are continuously sustained and integrated into the fabric of our scientific process.

95347 Examining the Impact of the BPCA: Promoting Pediatric Inclusion in Clinical Trials and Pediatric-Specific Drug Information

ABSTRACT IMPACT: It provides insight in the relationship between pediatrics and clinical research and how pediatric participation in CT translates to clinical significance in form of drug labels, which inform clinicians on how to prescribe pediatric medications. OBJECTIVES/GOALS: Assessing the extent that the Best Pharmaceuticals for Children Act (BPCA) advances pediatric inclusion in clinical trials (CTs) and the availability of pediatric-specific drug information METHODS/STUDY POPULATION: The BPCA provides the U.S. Food and Drug Administration (FDA) authority to solicit sponsors whose drugs may benefit pediatric populations. Participation is voluntary and provides additional market exclusivity and pediatric information. CTs that received marketing exclusivity from 2016-2018 under BPCA were reviewed using Clinicaltrials.gov to access the legislation’s impact. CTs were categorized according to eligibility: (1) pediatric and adult groups, (2) pediatrics, and (3) pediatric sub-groups. Studies were excluded for ambiguous age data. Studies open to both groups were evaluated for pediatric participation. Each drug was searched in DailyMed.com for published pediatric indications. RESULTS/ANTICIPATED RESULTS: Between 2016 - 2018, 22 drugs received marketing exclusivity under BPCA. Of the 196 CTs conducted for these drugs, 135 were available to adults and pediatrics, 10 were available to the entire pediatric population, and 51 were available to specific pediatric sub-populations. Exclusion criteria permitted only 118 of the CTs for assessment where eligibility included both pediatric and adult populations, of which 65 of these had less than 1% pediatric representation. Of the 22 drugs, 20 have pediatric indications. Over this three-year period, the number of CTs where adults and pediatrics were eligible were greater than CTs for pediatric only or pediatric subpopulations. DISCUSSION/SIGNIFICANCE OF FINDINGS: It is prevalent for BPCA compliant CTs to include both; 65% of drugs (13/20) with pediatric indications had more studies involving both groups than only pediatrics. Adequate pediatric CT representation is necessary for developing pediatric drug labeling with meaningful data for clinical indications.

The Best Pharmaceuticals for Children Act and Pediatric Research Equity Act reach the age of majority—An oncology perspective

The scarcity of adequate pediatric drug labeling information has long been problematic in the pediatric population, which may place children at risk for adverse drug effects. The ontogeny of infants, children, and adolescents over the course of the first two decades of life pose complex pharmacokinetic, dosing, administration, effectiveness, and toxicity-related questions that require specific investigation. Here, we review the history that led to the passage of the Best Pharmaceuticals for Children Act (BPCA) and Pediatric Research Equity Act (PREA), and provide commentary on issues relevant to pediatric oncology now and in the future.

A review of the experience with pediatric written requests issued for oncology drug products.

Pediatric anticancer drug development has numerous challenges. The Pediatric Research Equity Act (PREA) and the Best Pharmaceuticals for Children Act (BPCA) were passed to address pediatric drug development deficiencies in general. Until recently, the requirements for pediatric evaluation of most oncology products developed for adult cancers have been waived. Because children typically do not have the same type of cancers, which occur commonly in adults, or the indication or drug had been granted an orphan designation, PREA therefore has had no impact. Pediatric studies for labeling updates are largely done through BPCA by a written request (WR) issued by the Food and Drug Administration (FDA). Because the cancers that occur in pediatric and adult populations do not share the same etiology or natural history, there are limited opportunities to extrapolate adult efficacy and safety to the pediatric population. The characteristics of individual pediatric studies included in WRs have varied greatly over time. In this study, we searched WRs that were issued by the FDA since 2001. We found 40 such requests issued for oncology drugs and biologics, which had been accepted by sponsors. Clinical trials included in 23 of the WRs have been concluded, 19 have resulted in exclusivity, and three drugs that were studied have been approved for use in pediatric populations. Herein, we present the spectrum of WRs from a regulatory, study design, dosing, formulation, analysis plan, evidentiary standard of efficacy, and safety perspective. This provides information on requests issued in the past nearly 20years and studies that are completed. As WRs have provided the only regulatory mechanism to assure pediatric cancer drug development, this can potentially provide insight on how pediatric cancer drug development may change in the future.

Ethical Considerations for Pediatric Placebo-Controlled Trials: FDA Outcomes and Perspectives.

Placebo-controlled trials are the most rigorous method of evaluating the safety and efficacy of investigational treatments, yet the use of a placebo control in pediatric drug development is challenging and potentially controversial. Regulations provide additional protections for children participating in human subject research and limit the amount of risk to which children may be exposed without benefit (21 CFR 50, subpart D, Additional Safeguards for Children in Clinical Investigations). The objective of this paper is to describe the US Food and Drug Administration (FDA) experience with placebo-controlled trials conducted as part of pediatric drug development programs including compliance with 21 CFR 50, subpart D. Pediatric drug development programs conducted under the Best Pharmaceuticals for Children Act (BPCA) or the Pediatric Research Equity Act (PREA) between 2012 and 2018 were reviewed. Trials that utilized a placebo control were identified and trial characteristics and risk mitigation strategies were extracted from publicly available sources. During this time frame, a total of 266 products were studied under pediatric product development initiatives. Of those, 67 products (25%) were studied in 96 individual placebo-controlled trials in pediatric patients. The majority of these studies included approaches to minimize risk to children in the placebo arm, including 49 trials that utilized placebo as an add-on to known effective therapy for the disease and 48 trials that included rescue therapy in the study protocol. When designed and conducted appropriately, placebo-controlled trials meet requirements under current US federal regulations for the protection of children in research.

Combined Pediatric and Adult Trials Submitted to the US Food and Drug Administration 2012-2018.

Despite legislation incentivizing and requiring drug companies to conduct pediatric clinical trials, there still is a 9-year delay in drug approval for pediatric labeling after the initial adult drug approval. The aim of this study was to review the experience of the US Food and Drug Administration (FDA) with combined pediatric and adult trials as a means for expediting pediatric approval and labeling. Combined pediatric and adult trials submitted to the FDA from 2012 to 2018 were reviewed. Only the publicly available labels and reviews were utilized for this analysis. Combined trials were identified for 72 products, with a total of 156 combined adult and pediatric trials. The therapeutic areas with the largest number of combined trials were in pulmonology for products reviewed under the Best Pharmaceuticals for Children Act (BPCA) and/or the Pediatric Research Equity Act (PREA), and hematology reviewed under the Orphan Drug Act (ODA). All drugs that utilized combined pediatric and adult clinical trials were approved simultaneously for both the adults and that part of the pediatric population. A separate pediatric subgroup efficacy analysis was reported in 57% and 48% of products under BPCA/PREA and the ODA, respectively, with a separate safety analysis in 48% and 38% of these products. When considering both BPCA/PREA and orphan drug studies, all the combined pediatric and adult trials allowed concurrent approval and labeling for part of the pediatric population at the time of the adult approval.

4381 Examination of FDA Pediatric Regulations: Inclusion of Pediatric Populations in Clinical Trials, 2016 - 2018

OBJECTIVES/GOALS: To assess whether FDA regulations aimed at the pediatric population following the Best Pharmaceuticals for Children Act (BPCA) of 2002 are effective, this study examines the inclusion of the pediatric population in recent clinical trials for drugs used by both adult and pediatric groups. METHODS/STUDY POPULATION: From the U.S. Food and Drug Administration (FDA) a list of drugs approved between 2016 and 2018 was compiled. A search of clinicaltrials.gov provided corresponding clinical trials for the approved drugs. Study information such as eligibility criteria and demographics was gathered from each trial. From studies that included both adult and pediatric populations, the percentage of pediatric and adult subjects was calculated, resulting in values expressing exclusively pediatric subjects or the pediatric subjects as part of a category that included both populations (i.e. 18 years old). RESULTS/ANTICIPATED RESULTS: Between 2016 and 2018, 26 drugs were approved under the BPCA. From an assessment of 220 total studies, a lack of standardization is evident in terms of which ages constitute a particular pediatric sub-population even though guidelines for these sub-populations already exist under the BPCA. This lack of standardization resulted in the separate examination of each drug for pediatric inclusion. For the majority of the trials evaluated, 1% of the pediatric population was represented in trials that were open to both adult and pediatric populations. DISCUSSION/SIGNIFICANCE OF IMPACT: There is a need for more effective regulations and incentives for the pharmaceutical industry to standardize data presentation and better incorporate the pediatric population in clinical trials, especially for drugs targeted for this group.

Analysis of the Pediatric Age Groups Studied in Novel Drug Approvals

Background and Objectives: According to the Food and Drug Administration (FDA), prior to 2007 more than 80% of drugs approved in adults were being used off-label in pediatrics. In order to improve data on the use of drugs in children, Congress authorized two acts, the Pediatric Research Equity Act (PREA) and the Best Pharmaceuticals for Children Act (BPCA). The impact of these acts on the age groups for which new drugs are approved has not been evaluated. The objective of this study was to evaluate the …

Editorial introductions

Editorial introductions

Pediatric Antibacterial and Antifungal Trials From 2007 to 2017.

The impact of the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) on pediatric antibacterial or antifungal drug trials is unknown. Our objective was to identify and characterize trials conducted under the BPCA and/or the PREA. Pediatric antibacterial and antifungal drug trials with industry or US federal funding registered in clinicaltrials.gov from 2007 to 2017 were identified. Those conducted under BPCA and/or PREA were identified through US Food and Drug Administration and National Institute of Child Health and Human Development databases. Of 17 495 pediatric trials registered on clinicaltrials.gov between October 2007 and September 2017, 122 systemic antibacterial or antifungal drug trials with industry or US federal funding were identified. Of these 122 trials, 98 (80%) involved antibacterials only, 23 (19%) antifungals only, and 1 (1%) both antibacterials and antifungals. These represented <1% (122 of 17 495) of pediatric trials. Neither pediatric antibacterial nor antifungal drug trials commonly enrolled neonates 0 to 30 days old (30% [30 of 99] vs 42% [10 of 24], respectively). Pediatric antibacterial and antifungal trials were commonly industry funded (79% [78 of 99] and 83% [20 of 24], respectively). In total, 65% (79 of 122) of pediatric antibacterial and/or antifungal drug trials were conducted under BPCA and/or PREA. Researchers in trials conducted under BPCA and/or PREA, relative to non-BPCA and/or PREA trials, more often collected pharmacokinetic data (70% [55 of 79] vs 26% [11 of 43]). Although the majority of pediatric antibacterial and/or antifungal drug trials were conducted under BPCA and/or PREA, the overall number was low. Greater effort is needed to stimulate such trials.

Neonatal Safety Information Reported to the FDA During Drug Development Studies.

Relatively few neonatal drug development studies have been conducted, but an increase is expected with the enactment of the Food and Drug Administration Safety and Innovation Act (FDASIA). Understanding the safety of drugs studied in neonates is complicated by the unique nature of the population and the level of illness. The objective of this study was to examine neonatal safety data submitted to the FDA in studies pursuant to the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) between 1998 and 2015. FDA databases were searched for BPCA and/or PREA studies that enrolled neonates. Studies that enrolled a minimum of 3 neonates were analyzed for the presence and content of neonatal safety data. The analysis identified 40 drugs that were studied in 3 or more neonates. Of the 40 drugs, 36 drugs received a pediatric labeling change as a result of studies between 1998 and 2015, that included information from studies including neonates. Fourteen drugs were approved for use in neonates. Clinical trials for 20 of the drugs reported serious adverse events (SAEs) in neonates. The SAEs primarily involved cardiovascular events such as bradycardia and/or hypotension or laboratory abnormalities such as anemia, neutropenia, and electrolyte disturbances. Deaths were reported during studies of 9 drugs. Our analysis revealed that SAEs were reported in studies involving 20 of the 40 drugs evaluated in neonates, with deaths identified in 9 of those studies. Patients enrolled in studies were often critically ill, which complicated determination of whether an adverse event was drug-related. We conclude that the traditional means for collecting safety information in drug development trials needs to be adjusted for neonates and will require the collaboration of regulators, industry, and the clinical and research communities to establish appropriate definitions and reporting strategies for the neonatal population.

Editorial introductions

Editorial introductions

Modeling and simulation in pediatric drug therapy: Application of pharmacometrics to define the right dose for children

During the past decades significant progress has been made in our understanding of the importance of age-appropriate development of new drug therapies in children. Importantly, several regulatory initiatives in Europe and the US have provided a framework for a rationale. In the US, most notably the enactment of the Best Pharmaceuticals for Children Act (BPCA) and Product Research and Equity Act (PREA) has facilitated the studying of on-patent and off-patent drugs in children. The biggest challenge in pediatric studies is defining a safe and effective dose or dose range in a patient population that can span from premature neonates to adolescents. From a mechanism-based perspective, advances in the science of quantitative pharmacology and pharmacometrics have resulted in the development of model-based approaches to better describe and understand important age-related factors influencing drug disposition and response in pediatric patients. The application of modeling and simulation has been shown to result in better estimates of pediatric doses as evidenced by several studies, although the optimal approach is still being debated. The extrapolation of efficacy findings from adults to the pediatric population has streamlined the development process especially for studies in older children. However, a focus on developmental changes in neonates and infants as well as further developing a paradigm for conducting pharmacodynamic studies in neonates, infants, and children remain important unmet needs. In this overview we will review current approaches for age-appropriate dose selection and highlight ongoing efforts to define exposure-response and clinical outcome relationships across the pediatric age spectrum.

Patterns of Off-Label Prescribing in the Pediatric Intensive Care Unit and Prioritizing Future Research.

To characterize off-label prescribing among US pediatric intensive care units (PICUs), determine characteristics associated with off-label use, and identify medications in highest need for additional study. Medications prescribed for ≥1% PICU patients (age < 18 years) in 2010 were identified from 39 children's hospitals. Use in a patient younger than the Food and Drug Administration (FDA)-approved age for any indication was considered off-label. Hierarchical multivariable modeling was used to identify characteristics associated with off-label use, accounting for center effects. Highest-impact drugs were defined by: 1) high off-label use (off-label use in at least 5% of the PICU cohort), 2) high risk medication, and 3) high priority status by the FDA or Best Pharmaceuticals for Children Act (BPCA). A total of 66,896 patients received ≥1 medication of interest (n = 162) during their PICU stay. A median of 3 (interquartile range, 2-6) unique drugs per patient were used off-label. Those who received ≥1 drug off-label (85% of the cohort) had longer median PICU (2 days vs 1 day) and hospital (6 days vs 3 days) lengths of stay and higher mortality (3.6% vs 0.7%), p < 0.001. Factors independently associated with off-label drug use included: age 1 to 5 years, chronic conditions, acute organ failures, mechanical ventilation, arterial or venous catheters, dialysis, and blood products. Half of prescribed medications (n = 84) had been used off-label: 26 with significant off-label use, 30 high-risk medications, and 47 with high FDA/BPCA priority. The highest impact medications identified were: dexmedetomidine, dopamine, hydromorphone, ketamine, lorazepam, methadone, milrinone, and oxycodone. Most PICU patients are exposed to off-label medication use, with uncertain evidence. Future medication research in this population should focus on medications with high impact potential.

Best Pharmaceuticals for Children: How Far Have We Come?

IntroductionPharmaceutical policy initiatives , such as the Best PharmaceuticalsforChildrenAct,havemadesignificant strides in improving pediatrics-focused therapeutics. At the same time, there is still a relative paucityof clinical pharmacology data in regard to the pediatric population.Here, we review past and current legislative efforts in the UnitedStates, highlight current limitations, and suggest future practice andpolicy initiatives to optimize pediatric drug therapy.BackgroundIn response to mounting concerns regarding the safety andefficacy of medications used in pediatric populations, the BestPharmaceuticals for Children Act (BPCA) was enacted in 2002.