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New FDA Guidance Details How to Submit Pediatric Study Plans

New FDA Guidance Details How to Submit Pediatric Study Plans

In July, FDA published its final guidance on how sponsors should prepare and submit an initial pediatric study plan (iPSP). This update to the 2016 draft guidance offers FDA recommendations on the content and timing of pediatric study plan submissions, and the content and timing of requested pediatric study plan amendments.

Rise and Fall of the Pediatric Rule

In 1994, to address issues with inadequate testing and labeling regarding drug use in children, FDA started requiring manufacturers to examine existing data on marketed drugs and determine whether that data suggested they should add pediatric use information to labeling.

But FDA’s final rule did not ask drug makers to conduct further studies looking into the matter when existing data did not suggest adding pediatric use information. Most drug products still circulated the market with inadequate labeling and directions regarding safe and effective use in the pediatric population.

To further address the problem, the FDA Modernization Act of 1997 (FDAMA) began offering incentives for drug makers to conduct pediatric studies on drug products with patent protection or exclusivity. In late 1998, FDA published regulations requiring manufacturers to assess the safety and effectiveness of new drugs and biological products in pediatric patients – known as the Pediatric Rule.

In general, the Pediatric Rule required drug manufacturers to provide sufficient data supporting directions for pediatric use for approved indications. At the end-of-phase 2 meeting, FDA would advise sponsors on whether it would require pediatric study data before or after approval (end-of-phase 1 meeting for life-threatening disease indications).

The Pediatric Rule required sponsors to submit a proposed timeline for the pediatric studies (protocol design, enrollment, completion, data analysis) or information regarding plans to request a deferral or waiver. FDA recommended that sponsors submit the proposed timeline at least 1 month before the end-of-phase 2 meeting. Failure to comply with the Pediatric Rule resulted in FDA declaring the product a “misbranded or an unapproved new drug or unlicensed biologic.”

The 1997 FDAMA offered a 6-month extension to marketing exclusivity to give drug developers additional time to study products in pediatric populations. But off-patent products were not included. And manufacturers could still decline to perform pediatric studies. So in January 2002, the National Institutes of Health (NIH) was given authority over these gaps via the Best Pharmaceuticals for Children Act (BPCA).

BPCA authorized a research program to the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Under the BPCA, the NICHD was to identify and publish a list of high priority drugs for study in pediatric populations. It then sponsored relevant pediatric clinical trials and submitted results to FDA for consideration of labeling changes.

Under BPCA, FDA issues Written Requests to drug manufacturers to conduct pediatric studies. If a drug manufacturer declines a Written Request, the FDA can then refer the Request to NIH for clinical studies. NIH can also submit draft Requests or Proposed Pediatric Study Requests to FDA that outline the study design, population, and proposed endpoints.

In December 2000, the Association of American Physicians and Surgeons (AAPS), Competitive Enterprise Institute (CEI), and Consumer Alert filed a lawsuit in federal court claiming that FDA exceeded its statutory authority in issuing the Pediatric Rule. They claimed that the Rule conflicted with certain provisions of FDAMA and that Congress’ intent for FDAMA was that pediatric studies be voluntary.

FDA argued that the Federal Food, Drug, and Cosmetic Act (FD&C Act) granted the authority to issue the Pediatric Rule because it granted FDA authority to ensure adequate labeling for all claimed uses. FDA argued that many drugs are used by children despite having no pediatric labeling, and that labeling that fails to include customary or usual uses could be misleading (even if the drug maker does not initially claim such uses).

But in October 2002, federal district court Judge Henry H. Kennedy, Jr. found that FDA had indeed exceeded its statutory authority in issuing the Rule.

In reaching this decision, Judge Kennedy found that even though Congress did grant FDA the authority to ensure that drugs have adequate labeling for all claimed uses in the FD&C Act, the Pediatric Rule primarily impacts new drugs, which do not yet have any ‘customary or usual use.’ The FD&C Act did not grant FDA the authority to require testing for indications the manufacturer did not claim.

In addition, Judge Kennedy looked at the newly enacted BPCA and found that its voluntary approach conflicted with the mandatory approach of the Pediatric Rule. Here, Judge Kennedy reasoned that Congress was aware of the Pediatric Rule when it signed BPCA into law and actively chose a voluntary arrangement over a mandatory approach. The Court held that the Pediatric Rule was invalid. [Association of Am. Physicians & Surgeons, Inc. v. FDA, 226 F. Supp. 2d 204, 222 (D.D.C. 2002).]

PREA and Initial Pediatric Study Plans (iPSP)

One year after the ruling in Association of Am. Physicians & Surgeons, Inc. v. FDA, Congress signed the Pediatric Research Equity Act (PREA) into law. PREA included many of the provisions found in the Pediatric Rule. However, under PREA, sponsors no longer had to submit a proposed timeline or plan for submission of pediatric studies as a part of the IND application process.

In 2012, the Food and Drug Administration Safety and Innovation Act (FDASIA) added a provision to PREA that required sponsors preparing applications subject to PREA to submit an initial pediatric study plan. The iPSP serves to identify the need for pediatric studies and offer preliminary plans for studies.

FDASIA amendments to the FD&C Act require that FDA issue regulations and guidance on implementing PREA and other related provisions. In July 2020, FDA published its final guidance detailing current FDA recommendations on pediatric study plan submissions.

What Does an Initial Pediatric Study Plan Contain?

Under the FD&C Act, an iPSP must include:

  1. An outline of the pediatric study or studies that the sponsor plans to conduct (including to the extent practicable - objectives, design, age groups, relevant endpoints, statistical approach);
  2. Any requests for deferral, waiver, or partial waiver of pediatric studies (if applicable), along with supporting information; and
  3. Other information specified in FDA regulations.

In its final guidance, FDA recommends that sponsors include the following (if applicable) in the iPSP:

  • Overview of the disease/condition in the pediatric population
  • Overview of the drug or biological product
  • Overview of planned extrapolation to specific pediatric populations
  • Planned request for drug-specific waiver(s)
  • Planned request for deferral(s) of pediatric studies
  • Tabular summary of planned nonclinical and clinical development
  • Age-appropriate formulation development
  • Nonclinical studies
  • Clinical data to support design and/or initiation of studies in pediatric patient
  • Planned pediatric clinical studies
  • Timeline of the pediatric development plan
  • Agreements for pediatric studies with other regulatory authorities.

Of course, each case is unique. For example, a sponsor may need additional data on safety, efficacy, or potential endpoints before the sponsor can prepare a detailed study plan. FDA suggests, “In such cases, the outline of the pediatric studies should include a brief explanation for the lack of more detailed information.”

FDA acknowledges that pediatric study design and other variables may change as new data is obtained and suggests that the iPSP pediatric study plan be “based upon current knowledge of the drug and disease epidemiology.” Sponsors can also include information about plans to submit a future proposed pediatric study request (PPSR) separate from the iPSP, or submit amendments to agreed iPSPs to FDA at any time.

Who Must Submit an Initial Pediatric Study Plan?

Under the final guidance, sponsors must submit an iPSP if they are planning to submit a marketing application (or supplement) for any of the following:

  • New active ingredient
  • New indication
  • New route of administration
  • New dosing regimen
  • New dosage form
  • Drugs developed specifically for use in pediatric patients.

Biosimilar products that FDA has not deemed interchangeable with a reference product are considered to have new active ingredients.

Even if FDA has previously granted a waiver or deferral for the same drug under PREA, sponsors should submit an iPSP for any new application or supplement that is subject to PREA.

No iPSP is required if the drug is for an indication that has been granted orphan designation – unless:

  1. The application is for a new active ingredient intended to treat adult cancer that is directed at a molecular target determined to be substantially relevant to the growth or progression of a pediatric cancer, AND
  2. The sponsor plans to submit an original application on or after August 18, 2020.

When these two conditions are met, the sponsor must submit an iPSP – even if the indication has orphan designation.

When are Initial Pediatric Study Plans Due?

Under the final guidance, sponsors must submit the iPSP before the date they submit required assessments or investigation AND no later than 60 days after the end-of-phase 2 meeting date (or such other time as agreed upon with FDA in exceptional circumstances).

If there is no end-of-phase 2 meeting, sponsors should submit the iPSP before initiation of phase 3 studies (or combined phase 2 and phase 3 studies).

If there will be no phase 3 (or combined phase 2 and phase 3) studies, or if the studies will not be under IND, sponsors should submit the iPSP no later than 210 days before submitting the marketing application or supplement.

How Long is the Initial Pediatric Study Plan Review Process?

According to the final guidance, the total length of time for an iPSP review should not exceed 210 days. FDA should provide a written response to the iPSP (or meet with the sponsor to discuss the iPSP) within 90 days after submission. The sponsor then has 90 days to review the results, introduce concerns or negotiations, and submit an agreed iPSP.

Once FDA receives the agreed iPSP, it has 30 days to notify the sponsor that it confirms the agreement or is in disagreement. If FDA issues a disagreement, the iPSP is deemed a “Non-Agreed Initial PSP.” Sponsors should not submit marketing applications or supplements until they receive confirmation of FDA iPSP agreement.

Initial Pediatric Study Plans that do not include the required information – or planned waivers or deferrals that do not provide justification - may be deemed materially incomplete. When FDA determines an iPSP is materially incomplete, the sponsor has 30 days to correct the deficiencies and submit the complete iPSP. Upon submission, a new 210-day review period begins.

FDA states that it does not make formal decisions about granting waivers or deferrals of required pediatric studies or reports on cancer investigations directed at a molecular target relevant to the growth or progression of a pediatric cancer until marketing application approval. However, it does consider the information contained in agreed iPSPs when considering waivers or deferrals during marketing application review.

Further details on the information FDA requires or recommends that sponsors include in the iPSP, along with a suggested template for iPSP submission, can be found in the final guidance. Sponsors should contact an experienced FDA regulation and intellectual property specialist with questions regarding requirements and timelines related to their specific iPSP submission.


Gregory J. Glover MD JD is a patent attorney and non-practicing physician. A noted expert on developments and emerging conflicts in the pharmaceutical industry, Greg is an expert on regulatory IP issues.

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