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How to Successfully Prepare for Your Pediatric Study Plan

Although the implementation of laws surrounding the safety and efficacy of drugs and biologics started in the early 1900s, the inclusion of pediatric use in labeling has significantly lagged behind. Multiple factors have led to this lack of information including ethical, monetary, and feasibility challenges. The lack of data for pediatric use, however, leaves physicians with only empirical and experiential methods to dose children, leading to increased risks in this population.

The Food and Drug Administration (FDA) began increasing efforts to ensure that pediatric use information was provided in all drug labels in 1994. The FDA first published a rule that required manufacturers to determine whether existing data were sufficient to update drug labels for pediatric use. Unfortunately, this rule did not lead to substantial changes in labeling as it did not require any studies to be conducted if current data did not support pediatric use.

The FDA Modernization Act of 1997 and the Pediatric Rule of 1998 implemented additional incentives and requirements, respectively, for the conduct of pediatric studies. Legal battles, however, led to the Pediatric Rule being overturned in 2002.

Congress granted the FDA the authority to regulate pediatric studies in 2003 with its passage of the Pediatric Equity Research Act (PREA). Under PREA, all Sponsors are required to conduct studies to assess the safety and effectiveness of their products in pediatric populations. The FDA Safety and Innovation Act (FDASIA) of 2012 implemented requirements for all Sponsors to include a proposed timeline and design of pediatric studies during the investigational new drug (IND) stage; this plan is termed an initial pediatric study plan (iPSP).

Initial Pediatric Study Plan

An iPSP is required for all Sponsors that plan on submitting a marketing application for a drug that includes a new:

  • Active ingredient
  • Indication
  • Dosage form
  • Dosing regimen
  • Route of administration

One exception is if the drug or biologic has been granted orphan designation for the proposed indication at the time the iPSP is required (see Orphan Designation below).

Planning for an iPSP Submission

FDA agreement on an iPSP is required prior to the submission of a marketing application or supplement. Failure to include an agreed iPSP in a marketing application subject to PREA may be grounds for a refuse-to-file action.

Technically, the submission of an iPSP should occur no later than 60 days following the end of phase 2 (EOP2) meeting. Ideally, the iPSP should be drafted after EOP2 studies are completed but prior to the EOP2 meeting as this will allow for discussions around endpoint considerations for both the adult and pediatric studies. If the initial plans for an IND include a phase 3 study, the iPSP should be submitted as a pre-IND submission. It is strongly recommended that Sponsors schedule a pre-IND meeting prior to the submission of an iPSP in this case.

Timelines associated with an iPSP are long. When considering timelines for your program, budget in at least two months to draft an iPSP (the FDA guidance “Pediatric Study Plans: Content of and Process for Submitting Initial Pediatric Study Plans and Amended Initial Pediatric Study Plans” outlines the expected contents). Make sure that all functional areas are available for input including toxicology, manufacturing, clinical, pharmacokinetics, and pharmacometrics. The total review period with the FDA is 210 days.

Chart outlining the iPSP submission process for the FDA

Any issues with a submission, such as a materially incomplete iPSP or non-agreed iPSP, will add weeks to months to this timeline. Subsequent reviews of non-agreed iPSPs lack any statutory timeline requirements, so it is important to ensure that the first iPSP versions are well thought out and as complete as possible. Even though the FDA may agree to an iPSP, it is not formally approved until the marketing application is submitted.

Orphan Designation

Orphan designation applies to drugs or biologics that are intended for the treatment, prevention, or diagnosis of a disease or condition that affects less than 200,000 people in the United States. According to the Pediatric Study Plans guidance, Sponsors are exempt from submitting an iPSP if their drug or biologic has been granted orphan designation for the proposed indication at the time the iPSP is required. However, some exceptions now apply.

On August 18, 2017, the RACE for Children Act was incorporated as Title V of the 2017 FDA Reauthorization Act (FDARA) to amend PREA. According to this act, all new drugs and biologics that are “intended for the treatment of adult cancers and are directed at a molecular target substantially relevant to the growth and progression of a pediatric cancer” are required to conduct pediatric studies, regardless of orphan status.

To assist in determining whether a drug or biologic will be affected by this regulation, the FDA Pediatric Oncology Program has released a Pediatric Molecular Target List which differentiates targets based on their relevance to the growth or progression of pediatric cancers. This rule applies to any new applications with planned submission dates after August 18, 2020.


Plans for full or partial extrapolation of efficacy from adult to pediatric populations or from one pediatric population to another should be included in an iPSP. Prior to discussing extrapolation, it is key to provide a clear description of the similarities and differences between adults and pediatric populations that pertains to the drug, indication, epidemiology, and the unmet medical need. If the disease and effects of a drug are sufficiently similar between adults and pediatrics, it may be possible to fully extrapolate efficacy. The majority of iPSPs include plans for partial extrapolation of efficacy (with differences in dosing).

In almost all cases, safety cannot be extrapolated from adults, but safety data can be leveraged (particularly if the mechanism is well known and there is an exposure-response relationship). If the ability to extrapolate effectiveness from adults to children is not known or is not present, the iPSP must include plans to establish effectiveness with at least one placebo-controlled trial. More often than not, Sponsors will be required to run a small study to gain safety information even if they can demonstrate similar efficacy across populations.

One of the goals within the extrapolation section is to discuss how pediatric subjects will be dosed. The pediatric dose is typically determined based on modeling and simulation. It is important to note that modeling and simulation results do not necessarily need to be included in the iPSP. It is acceptable to include only the plans for these analyses as the dosing and study design will not be approved until the Agency reviews the actual protocol.

Waivers and Deferrals

The waivers section of the iPSP is where companies can request a waiver or, more likely, a partial waiver for studying certain age groups if any of the following criteria are met:

  • Necessary studies are impossible or highly impracticable
  • There is evidence strongly suggesting that the drug or biological product would be ineffective or unsafe in pediatric age groups
  • The drug or biological product does not represent a meaningful therapeutic benefit over existing therapies for pediatric patients and is not likely to be used in a substantial number of pediatric patients

The deferral section of the iPSP is where companies request deferrals of pediatric assessments in some or all pediatric groups until after marketing approval or until data from ongoing or planned studies are complete.

Remaining Sections of the iPSP

The remaining sections of the iPSP describe results from completed pre-clinical and clinical studies, study designs of planned and ongoing pre-clinical and clinical studies, and the timelines for conducting these studies.

The other key feature described in the iPSP is planned pediatric formulation(s). It is important to plan ahead for pediatric formulations (e.g., dispersible tablets, suspensions) because the formulation could be the rate-limiting step to conducting pediatric studies. Typically, when a new pediatric formulation is planned, a relative bioavailability study will be conducted in adults first.

While the formulation does not have to be bioequivalent to the adult formulation, there is a need for the pediatric dose to be adjusted based on body weight (or age) and the difference in relative bioavailability, if there is one. If the relative bioavailability of the pediatric formulation is very low compared to the adult formulation, then multiple tablets must be administered to pediatric patients, creating a feasibility issue.

Other Important Considerations

  • All pediatric age groups need to be addressed in an iPSP
  • The submission of an iPSP is required even if a drug or biologic is being developed for use in pediatric populations
  • A new iPSP needs to be submitted even if a new application is being submitted for a drug or biologic that was previously approved or was granted a waiver or deferral under PREA
  • iPSPs are required for biosimilars that are not considered interchangeable with the reference product
  • Amendments to an iPSP within 210 days of a marketing application submission that delay or defer previously agreed pediatric studies may result in a refuse-to-file


Although the regulations surrounding pediatric studies have been around for years, the submission of an iPSP can still catch many Sponsors off-guard when preparing for their marketing applications or heading to their end of Phase 2 meetings.

The FDA guidance for Pediatric Study Plans is a great place to start as it provides clear expectations for the submission and preparation of iPSPs; however, it can still be challenging to write and reach an agreement with the Agency.

Contact Nuventra today to learn more about how we can assist with your iPSP needs.

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