Pediatric Therapeutics and Regulatory Science Initiative

Pediatric policy and regulation: Over the past two decades, policymakers in the US and Europe have passed legislation and regulations specifically aimed at promoting the development of pediatric drugs and devices and increasing the evidence available to inform clinical decision-making. Comprehensive study of the implementation and impact of these policies supports data-driven assessments of strengths and limitations of current programs and informs proposals for policy reforms.

Utilization and health outcomes: The Initiative leverages expertise in pediatric pharmacoepidemiology to analyze medication utilization patterns and treatment outcomes in large cohorts of pediatric patients. These types of studies are an essential tool in defining the effectiveness of drugs and devices in real-world settings and identifying inequities and variations in medication use, non-evidence-based practices, and adverse events associated with new treatments.

Clinical trial methods and ethics: Pediatric trials face numerous ethical, financial, and practical challenges, including concerns around exposing children to risk, low prevalence of many childhood diseases, and inadequate financial investment in pediatric-focused product development. This has led to underrepresentation of pediatric patients in clinical trials and widespread off-label use of many medicines and devices studied only in adults. Patient-centric approaches are needed to design and prioritize pediatric trials that are ethical and safe, and reflect areas of greatest clinical need.

Legislative outcomes:

Legislators and regulators have made efforts to address the inattention paid to the testing of prescription drugs in children. More than 20 years after the first of these efforts was enacted, we reviewed in the New England Journal of Medicine the outcomes of this legislative reform to inform what future efforts may be needed to promote the availability of prescribing information for children.

To quantify the impact of these policies, we have performed a series of analysis assessing pediatric drug policies. One study, published in Health Affairs, indicates that many drugs deemed relevant to children continue to lack appropriate labeling to support use in pediatric populations. In all, nearly two-thirds of new drug and biologic indications with potential pediatric applications lack pediatric prescribing information at five years after FDA approval.

Pediatric postmarketing studies:

Many medicines prescribed to children have not been studied or formally approved for pediatric use and the FDA relies on postmarketing studies to generate pediatric labeling data. In a study published in JAMA Pediatrics, we examined over 200 required pediatric postmarketing studies and found that only a third of studies were actually completed. As a result, approximately 60% of drugs continued to lack pediatric prescribing information after a median of 7 years since market approval.

In a collaboration with the European Medicines Agency, we assessed the impact of the EU’s Pediatric Regulation, which entered into force in 2007. The first study from this project, published in PLOS Medicine, analyzed the completion and results of over 300 pediatric clinical trials, indicating similar challenges with the timely completion of pediatric trials. Another study, published in Lancet Child and Adolescent Health, examined the availability of pediatric information for new medicines approved by the EMA, highlighting particular challenges with increasing pediatric labeling for the youngest age groups.

Pediatric medical devices:

Although medical devices can be lifesaving for a variety of diseases, few devices have been developed specifically for children. Studies published by our group in Pediatrics and JAMA Pediatrics have examined pediatric device trials and FDA approval of medical devices to characterize the evidence underpinning pediatric device use and approvals. Overall, despite dedicated programs to increase pediatric medical device development, there continues to be a dearth of devices that are evaluated and approved for pediatric populations compared to adults.

A focused analysis of cardiovascular devices, published in JAMA, examined all cardiovascular devices approved by the FDA since 1977 and showed that less than 10% had been approved for use in pediatric patients. Further, most cardiovascular devices with pediatric labeling were approved on the basis of clinical trials that had studied only adults.

Another analysis, focused on FDA approval of AI/ML-enabled devices, has also underscored the exclusion of pediatric patients in the development of these radibly expanding technologies.

Prescription medication misuse:

High rates of prescription drug misuse among adolescents have put renewed focus on ensuring judicious use of controlled medications to limit adverse outcomes related to misuse, addiction, and overdose. Using data from several large national healthcare datasets, we demonstrated encouraging decreases in prescribing rates of benzodiazepines and other controlled substances to adolescent patients (see publications in JAMA Pediatrics here and here). However, a number of concerning trends persist, including concurrent prescribing of opioids and benzodiazepines as well as high rates of use of benzodiazepines for indications with limited clinical evidence of efficacy.

A number of laws and policies have been implemented by US States to decrease the amount of opioid medications prescribed and distributed. Based on a series of analyses using national data on opioid poisonings, we have demonstrated that these state-level policies may be reducing opioid poisoning and overdoses in children and adolescents. One area that warrants additional examination, is the impact of naloxone access laws and how these might be further strengthened to ensure they are benefiting adolescents.

US legislative initiatives to increase pediatric drug development

Best Pharmaceuticals for Children Act (BPCA)

BPCA was implemented in 2002 and provides an incentive for pharmaceutical companies to perform pediatric studies and improve the pediatric labeling of selected drugs and biologics. More on BPCA

Pediatric Research Equity Act (PREA)

Under PREA, the FDA can require study of certain drugs and biologics in children using appropriate pediatric formulations. PREA was passed in 2003 and was the first legislation to explicitly require that drugs and biologics developed for adults also be studied in children. More on PREA

Analyses of this legislation by our group, published in JAMA, JAMA Pediatrics, and Pharmacoepidemiology and Drug Safety.

Rare Pediatric Disease Priority Review Voucher

This program was designed to promote the development of new drugs and biologics for the prevention and treatment of rare diseases affecting primarily children. It was authorized in 2012 and extended through 2020. More on Rare Pediatric Disease Priority Review Program

Our analysis of this program, published in Health Affairs.

Research to Accelerate Cures and Equity (RACE) for Children Act

The RACE Act, approved in 2018, requires pharmaceutical companies developing oncology products for adults to also develop these drugs for children if the molecular target of the drug is relevant to a children’s cancer. More here and here on RACE for Children Act

Our analysis of this Act, published in Journal of the National Cancer Institute.

US legislative initiatives to increase pediatric device development

Pediatric Medical Device Safety and Improvement Act

This 2007 legislation was passed to incentivize pediatric medical device development and increase the number of medical devices that have been studied in children and are specifically labeled for use in this population. Read more

Analysis of this act by our group, published in Pediatrics

Food and Drug Administration Resources

The FDA’s home page for pediatric activities.

FDA Pediatric Labeling Database

This database provides details on all drug and biologic labels that were modified to add pediatric information in response to pediatric legislative initiatives. View database

FDA Pediatric Clinical Trials Database

Clinical studies listed in this database were performed under pediatric legislative initiatives and lead to pediatric labeling changes. View database

European Medicines Agency Resources

Pediatric Regulation

The European Medicines Agency’s (EMA) Pediatric Regulation was implemented in 2007 with the aim of ensuring that medicines used in children are safe and effective and include appropriate labeling information. Read more

Pediatric Investigation Plans Under the Pediatric Regulation

Pediatric Investigation Plans are developed in conjunction with pharmaceutical companies and outline a development plan to ensure necessary data are generated to support approval of the product for children. Read more

Pediatric Clinical Trials

This trial registry includes information on all clinical trials performed as part of a pediatric investigation plan or to support pediatric use of a medicine with EU marketing authorization.  Read more