Pediatric Research Equity Act Research Articles

Evaluation of FDA Labeling Changes Related to PREA Safety-Waivers.

The Pediatric Research Equity Act (PREA) gives the US Food and Drug Administration (FDA) authority to require pediatric studies for drug and biologics products under certain circumstances and to waive this requirement in some, or all, pediatric ages. When studies are waived for safety, PREA stipulates the safety issue must be described in labeling. This study assessed the rate of including waiver-related safety information in labeling. FDA databases were reviewed to determine the number of safety-related pediatric study waivers and issued from December 2003 through August 2020, and corresponding labeling to establish when relevant safety information was included. Descriptive comparisons were conducted across Cohort 1: December 2003-2007, Cohort 2: 2008-2011, Cohort 3: 2012-2015, and Cohort 4: 2016-August 2020. One hundred sixteen safety waivers were issued [Cohort 1 (n = 1); Cohort 2 (n = 38), Cohort 3 (n = 37), and Cohort 4 (n = 40)] for 84 unique drugs or biologics. Most (106 of 116; 91%) waiver-related safety issues were described in labeling [Cohort 1 (1 of 1), Cohort 2 (33 of 38), Cohort 3 (33 of 37), and Cohort 4 (39 of 40)]. Safety waivers were most common in patients ≤ 17years (n = 40) and least common in patients ≤ 6months (n = 15). Products for infections (n = 32) were the most common group receiving safety waivers; 17 for non-antiviral anti-infective products including treatments for dermatologic infestations/infections, and 15 for antiviral products. The data confirm that FDA consistently describes waiver-related safety information in drug/biologic product labeling since the inception of PREA in December of 2003.

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.

Clinical trial considerations for pediatric cancer drug development

ABSTRACT Oncology has been one of the most active therapeutic areas in medicinal products development. Despite this fact, few drugs have been approved for use in pediatric cancer patients when compared to the number approved for adults with cancer. This disparity could be attributed to the fact that many oncology drugs have had orphan drug designation and were exempt from Pediatric Research Equity Act (PREA) requirements. On August 18, 2017, the RACE for Children Act, i.e. Research to Accelerate Cures and Equity Act, was signed into law as Title V of the 2017 FDA Reauthorization Act (FDARA) to amend the PREA. Pediatric investigation is now required if the drug or biological product is intended for the treatment of an adult cancer and directed at a molecular target that FDA determines to be “substantially relevant to the growth or progression of a pediatric cancer.” This paper discusses the specific considerations in clinical trial designs and statistical methodologies to be implemented in oncology pediatric clinical programs.

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.

Postmarketing requirements for drugs approved by the Food and Drug Administration for the treatment of solid tumor cancers, 2010-2019.

e13597 Background: In recent years, efforts to improve the efficiency and speed of drug development and approval have driven a surge of Food and Drug Administration (FDA) approvals for cancer drugs. For many cancer therapies, the serious or life-threatening nature of the condition and unmet medical need confers eligibility for expedited programs. Many cancers are also rare diseases, and the increasing use of precision medicine principles to define cancer types further contributes to smaller trial sizes. With limited clinical evidence at the time of approval, cancer drugs may be subject to a greater burden of postmarketing requirements (PMRs). We analyzed PMRs for solid tumor therapies approved by the FDA over the past decade. Methods: The FDA’s novel drug approvals (2010-2019) were reviewed to identify drugs receiving primary approval for solid tumor indications. Approval letters were accessed via the Drugs@FDA database and analyzed for PMRs required under accelerated approval (AA), the Pediatric Research Equity Act (PREA) and the FDA Amendments Act of 2007 Section 505(o) (505(o)). Data are presented using descriptive statistics. Results: A total of 60 drugs received primary approval from the FDA for solid tumor indications between 2010 and 2019 (20 [33.3%] received AA, 33 [55.0%] received orphan designation, and 45 [75.0%] received Fast Track or Breakthrough Therapy designation). The proportion of drugs receiving AA doubled between the period 2010-2014 and 2015-2019 (Table). Of the 60 drugs approved, 52 (86.7%) received a total of 180 PMRs. All 20 drugs approved under AA received PMRs, with a total of 25 PMRs issued under AA. Data from new clinical trials were required for 22 (88.0%) of the 25 PMRs. No PMRs were issued under PREA. Additional safety data required under 505(o) comprised the largest proportion of PMRs; 155 total PMRs (86.1% of all PMRs) were issued for 45 (75.0%) of the drug approvals. Pharmacokinetic or other clinical safety data were required for 96 (61.9%) of the 155 PMRs. Conclusions: More than three-quarters of the cancer drugs approved for the treatment of solid tumors in the past 10 years were issued PMRs, with the majority requiring new safety data. The results of this study indicate that PMRs represent a critical mechanism by which FDA collects safety and efficacy for solid tumor therapies, and underscore the importance of PMR fulfillment. Post-marketing requirements (PMRs) for solid tumor drugs approved 2010-2019.[Table: see text]

Regulatory Approval Scenario of Biosimilars in Pediatric Patients in the United States and European Union.

Regulatory agencies of the USA and European Union (EU) have introduced multiple guidelines in the last decade to standardize and accelerate biosimilar development. As a result, a large number of biosimilars are being approved in the USA and EU. In the present review, we identified the biosimilars and their corresponding reference biologics approved for pediatrics in the USA and EU, and then assessed their approval details. In the USA, a biosimilar applicant needs to submit an initial pediatric study plan under the Pediatric Research Equity Act (PREA). We found that the PREA requirements of a pediatric assessment for biosimilars were waived where the reference biologics were not approved for one or more pediatric age groups for an indication. The PREA requirements of a pediatric assessment were deferred if the indication was under orphan drug exclusivity or a pediatric formulation was not available. Excluding the waiver and deferral scenarios, biosimilars were approved for the same pediatric indications as those of the reference biologics based on scientific justification extrapolation from the pediatric information of the reference biologics to biosimilars. The applicants were asked to submit a pediatric assessment in the deferred indication and/or develop a dedicated formulation that can ensure accurate dose delivery in pediatric population, as applicable. In the EU, pediatric assessments were not required for biosimilars; hence, all biosimilars (except rituximab) have been approved for the same indications as those of the reference biologics. Biosimilar developers need to be aware of the possible requirement of a pediatric study plan, development of pediatric drug delivery devices, and requirement of human factor studies for a device, to avoid delay in approval of biosimilars in the USA.

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.

Impact of Regulatory Incentive Programs on the Future of Pediatric Drug Development.

Surveys evaluating industry experience with performing pediatric studies under the Best Pharmaceutical for Children Act (BPCA) and Pediatric Research Equity Act (PREA) regulatory regime were conducted by Tufts Center for the Study of Drug Development (Tufts CSDD) in 2000, 2006, and 2016. These survey results are being used to assess the future impact of regulatory incentive programs on generating pediatric specific labeling information and development of age-appropriate drug formulations. A second perspective will be provided through the experience and expertise of neonatal/pediatric clinicians and researchers with a focus on the urgent need for the study of new and existing drugs in this vulnerable population (especially with 90% of drugs in neonates still being used off-label). This group will also address the impact of existing regulations and the likely trajectory of future pediatric drug development efforts after nearly 2 decades of regulatory incentives (both mandatory and voluntary). Finally, this review will provide input on approaches that are needed to continue to advance pediatric drug development with an emphasis on rare diseases.

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 …

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.

Pediatric drug information available at the time of new drug approvals: A cross-sectional analysis.

Greater than 50% of drugs lack pediatric labeling information, resulting in widespread "off-label" use in children. To increase pediatric prescribing information, the Pediatric Research Equity Act (PREA) was passed in 2003, requiring new drug applications to include pediatric assessments. We evaluated the study of new drugs in children since PREA was implemented. We performed a cross-sectional analysis of new drug applications submitted to the FDA from December 2003 to July 2012, using publicly available documents at Drugs@FDA. We calculated the proportion of new drugs that included a pediatric assessment at the time of approval and at a final review performed in July 2016. We identified 92 new drugs requiring pediatric assessments. Only 20 (21.7%) had been fully studied in children at the time of approval, while 9 (9.8%) had been partially assessed, and 63 (68.5%) did not have pediatric data. Among drugs approved without pediatric assessments, 4.2% met FDA deferral deadlines and 34.9% eventually submitted pediatric data. At the time of our final review, allowing for a mean of 8.6years since drug approval, 57.6% of new drugs had not been fully assessed in children. The mean time between approval in adults and availability of pediatric data for drugs approved without pediatric assessments was 6.5years. These results represent a comprehensive evaluation of the study of new drugs in children and demonstrate that many drugs continue to be approved without pediatric data. Our findings serve to inform approaches to strengthen adherence to PREA requirements.

Issues Impacting Therapeutic Outcomes in Pediatric Patients: An Overview

The quest for achieving optimal therapeutic outcomes in pediatric patients has evaded the healthcare professionals for long and often lack of child specific dosage forms and the associated events that follow with it have been considered to be major contributor towards suboptimal outcomes. Consequently, there have been sustained efforts over the years to address this issue with the enactment of legislations like Best Pharmaceutical for Children Act (BPCA), Pediatric Research Equity Act (PREA) and Pediatric Regulation by European Union (EU) to incentivise the participation of pharmaceutical industry towards development of child friendly dosage forms. Initiatives taken in past by organisations like World Health Organisation (WHO) and Drugs for Neglected Diseases Initiative (DNDi) to spur the development of child friendly dosage forms has helped to address issues pertaining to management of Human Immunodeficiency Virus (HIV) and malaria in pediatric patients. Present efforts aimed at developing child friendly dosage forms include oro-dispersible platforms including thin films and mini-tablets. Despite these leaps and advancements in developing better dosage forms for children, lower therapeutic outcomes in pediatric patients continue to remain an unresolved issue because of detrimental effects of additional factors such as parents understanding of label instructions and complexities involved in executing pediatric clinical studies thus requiring a concerted effort from pharmaceutical companies, academic researchers, parents and healthcare providers to work for better treatment outcomes in children.

Ensuring safe and effective medication use in pediatric patients.

This is a tremendous honor to receive peer recognition carrying the name of late Dr Sumner Yaffe. I was fortunate to have worked with him over many years through professional organizations and as a part of the pediatric pharmacology research units (PPRUs). Dr Yaffe established pediatric pharmacology programs in Buffalo and Philadelphia and made important contributions to enhance pediatric care with his research, practice, and teaching. He led the development of PPRUs and the neonatal networks, and was a force behind the framing of what became the Best Pharmaceuticals for Children Act (BPCA) and Pediatric Research Equity Act (PREA). He was indeed a visionary leader and mentor in the field of pediatric pharmacology. The objectives of my presentation today are to briefly share my background, reflect on our work, and discuss potential opportunities to advance pediatric pharmacy, pharmacology, and therapeutics.

Drug Development

Drug Development