What the FDA Expects from Your Pediatric Drug Program

What the FDA Expects from Your Pediatric Drug Program

Historically, 80 percent of medicines used in children had little to no data guiding prescribers on proper use. To address this market failure, regulatory legislation for drug development in pediatric patients was passed worldwide over the past decade. The number of drugs tested in and labeled for children has increased dramatically as a result. In this blog post, I’ll discuss the latest FDA regulations on pediatric drug development.

The FDA’s guidance for the pharmaceutical industry

The major pieces of US regulation on developing medications for children are:

  • The Best Pharmaceuticals for Children Act (BPCA), which acts like a “carrot.” It provides an incentive for drug companies to conduct FDA-requested pediatric studies by granting an additional six months of marketing exclusivity.
  • The Pediatric Research Equity Act (PREA), which serves as the “stick.” It requires pharma companies to study investigational drugs in children under certain circumstances.
  • The Food and Drug Administration Safety and Innovation Act (FDASIA) which makes permanent the BPCA and PREA.

So what does FDASIA mean for sponsors?

In 2012, President Obama signed FDASIA into law. FDASIA provides clarity on the process for submitting initial pediatric study plans (PSPs) and amended PSPs, which was first described in the FDA’s Guidance for Industry on Pediatric Study Plans. FDASIA defines who must submit an initial PSP (iPSP), when it must be submitted, and what it should include. After the end-of-phase 2 (EOP2) meeting, you have 60 days to submit your iPSP to the FDA. That’s an important date. If you don’t submit your PSP and are out of compliance, your company may be placed on a non-compliance list on the FDA website. FDASIA also defines what should be included in any requested amendments to an agreed-upon iPSP. Lastly, it specifies a template that should be used to develop an iPSP submission.

The iPSP template

The iPSP template has 12 sections. Here are the sections that contain its major requirements:

  • Section 1—Overview of the Disease Condition in the Pediatric Population: In this section the sponsor must provide a brief summary of the pathophysiology of the disease, methods of diagnosis, and currently available treatments and/or prevention strategies in the pediatric population including neonates. They also should discuss the incidence and prevalence of the disease in the overall population and the incidence and prevalence in the pediatric population.
  • Section 3—Overview of Planned Extrapolation to Specific Pediatric Populations: In this section, the sponsor must explain their plans for extrapolating efficacy data from adults to pediatrics and provide any available supporting data for all age ranges from which efficacy will be extrapolated. The sources for this supportive data can include sponsor data, published literature, and expert panels and workshops. Extrapolation of efficacy for other drugs in the same class, if previously accepted by the FDA, can also be considered supportive information.
  • Section 4—Request for Drug-Specific Waiver(s): The sponsor must provide their plans and justification for requesting a waiver (either full or partial) of the requirement to provide data from pediatric studies. Requested waivers in the PSP will not be formally granted or denied until the application is approved. If studies are waived because of evidence that the drug would be ineffective or unsafe in any pediatric age group, this information must be included in the product labeling. Generally, this information is in the Pediatric Use subsection of labels. Waivers to study an investigational drug in pediatric patients are hard to acquire whereas deferrals are easier to obtain.
  • Section 5—The Summary Plan for Non-clinical and Clinical Studies: In this section, the sponsor lists their planned pediatric clinical and non-clinical studies. The pediatric clinical studies include both pediatric pharmacokinetic studies to determine an appropriate dose based on an established pharmacodynamic endpoint and clinical effectiveness and safety studies.
  • Section 6Pediatric Formulation Development: In this section, the sponsor provides details of any pediatric-specific formulation development plans, if appropriate, including whether the formulation that is being developed can be used for all pediatric populations. It also includes information on age-appropriate formulations for all pediatric age groups that will be studied. Sponsors also should provide details about the size of all planned capsules or tablets, to the extent practicable, to be used in pediatric studies.

I’ll cite a recent letter to a sponsor developing a pediatric bowel prep drug from the FDA’s Division of Gastroenterology and Inborn Errors Products as an example of the evolving attitude towards pediatric drug development. The letter cites the requirement to include an Agreed iPSP. Then, they encourage the sponsor to obtain an Agreed iPSP before submitting a marketing application. The letter ends with a warning that “failure to include an Agreed iPSP in a marketing application subject to PREA may be grounds for a Refuse-to-File (RTF) Action.” To me, this suggests that the agency is starting to take a harder line with sponsors who do not abide by PREA requirements. It’s more threatening than merely being placed on a non-compliance list on the agency’s website. The possibility of receiving an RTF for a product should certainly be an incentive to take pediatric drug development requirements seriously.

The push to leverage pharmacometrics

Up to 50% of pediatric safety and effectiveness trials are not interpretable. Unsuitable designs lead to slow enrollment and low retention, as well as higher costs and approval delays.

Perdita Taylor-Zapata, MD
National Institute of Child Health and Human Development

The high failure rate of pediatric clinical trials poses a daunting challenge to the pharmaceutical industry. Pharmacometrics is an important tool to help inform smarter clinical trial design that maximize insights while minimizing trial duration, number of subjects needed, and number of blood samples taken. The FDA has set a target that 100% of all pediatric trials will have modeling and simulation associated with them by 2020. My company, Paidion, partners with Certara to leverage modeling and simulation for hundreds of studies in early and late pediatric clinical research.

To learn more about how pediatric considerations fit into the overall drug development program, please watch my webinar. Let me know what you think in the comments section!

Barry Mangum

About the Author

Barry Mangum

Founder and CEO, Paidion Research

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As Paidion’s Founder and CEO, Dr. Mangum is responsible for their vision of profound and meaningful change in global pediatric clinical research. Paidion is catalyzing change in an old paradigm and laying the groundwork for developing safe and effective medicines for children. Responsible for partnering with clients to implement clinical trials for all phases of pediatric drug development, Dr. Mangum brings decades of pediatric clinical research expertise to Paidion. His extensive academic experience includes serving as faculty and researcher in pediatrics and clinical pharmacology/pharmacotherapy at Duke's and UNC's medical schools. His corporate experience includes serving as Senior Director of Pediatric Clinical Development Services at Quintiles. He has numerous publications, presentations, and memberships, including co-authorship of NeoFax: A Manual of Drugs Used in Neonatal Care, the leading guide for dosing neonatal medications in the US, as well as the NeoFax software package and mobile device app.