FDA generates guidance documents to convey their current thinking related to areas they regulate. Currently there are more than 2700 listed on their website. Often, guidance documents are produced that summarize and expand upon information included in prior postings. Several guidance documents have been issued this year summarizing considerations for the development of drugs in pediatric patients:
FDA recognizes four distinct pediatric patient populations:
The Food and Drug Modernization Act of 1997 (FDAMA) established incentives for conducting trials in pediatric patients. Congress subsequently passed the Best Pharmaceuticals for Children Act (BCPA, 2002) and Pediatric Research Equity Act (PREA, 2003).
In addition to codifying incentives for conducting studies, sponsors are obligated to submit a pediatric assessment to accompany an NDA or BLA submission. This is typically done through the filing of an initial Pediatric Study Plan (iPSP).
FDA issued a guidance document in 2020 detailing the process for submission of a pediatric study plan including expectations for content.
The review period for an iPSP can be up to 210 days, incorporating FDA review and comments, revisions by the sponsor and resubmission, and FDA secondary review and plan confirmation. To ensure the plan is in place by the time of NDA submission, the initial plan should be submitted within 60 days of the end-of-phase 2 meeting.
The iPSP needs to describe plans for each of the pediatric populations and the timing for when studies will be conducted. Requests for a deferral, typically until after pivotal studies in adults are completed or after drug approval, can be made and justified in the plan. Likewise, a waiver may be requested if studies are impractical due to the nature of the disease, or an unfavorable benefit-risk exists. Note: applications for drugs that have orphan designation are exempt from having to submit an iPSP.
However, the FDA Reauthorization Act of 2017 (FDARA) amended PREA for targeted oncology drugs. Applications for targeted oncology drug approval now require an iPSP evaluating pediatric cancer indications irrespective of orphan drug status. For instance, application for approval of a drug for an orphan oncologic disease that only occurs in adults such as a BRAF inhibitor for melanoma would require an iPSP for glioma in children.
FDA maintains lists of those molecular targets that do or do not require an iPSP.
In March 2019 FDA issued a guidance document discussing how to incorporate pediatric dosing information into product labeling. The document describes consistent placement of information to assist health care providers in the safe use of drugs in pediatric patients.
In general, whatever is known about use in pediatric populations should be placed in the subsection 8.4 “Use in Specific Populations: Pediatric Use”. If studies have been conducted that FDA has concluded support use of the drug, appropriate information should also appear in sections describing the data derived from studies.
Negative or incomplete studies should not appear elsewhere in labeling unless there is a contraindication for use, which could be placed in the Contraindication, Boxed Warning, and Warnings and Precautions sections.
A separate guidance specific to clinical pharmacology was issued in 2022 which emphasizes the need to understand drug disposition in individuals with the disease being treated.
The practical and ethical considerations for inclusion of pediatric patients in clinical trials are spelled out in 21 CFR part 50, Subpart D and are included in the draft guidance issued by FDA in 2022.
Perhaps the most important element of that is the condition that any investigation involving greater than minimal risk requires the intervention to provide the “prospect of direct benefit” to participants.
This presents unique challenges of balancing what is likely to be a safe dose in pediatric patients with what could possibly be an effective dose. Strategies to identify an appropriate dose commonly include prior testing in adults. When testing in adults is not feasible (e.g., a gene therapy for a life-threatening pediatric disease) support needs to come from preclinical evaluations or related clinical trials.
In addition to requirements for conducting clinical trials in pediatric patients, congress has enacted several incentives for doing so. A six-month extension of product exclusivity can be granted if pediatric studies are completed that comply with a written request for studies from the FDA. Note: this is not the same agreement contained in an iPSP.
If the indication is eligible for Orphan Drug designation, that is there are less than 200,000 patients with the condition in the US, incentives include a waiver of PDUFA filing fees for the NDA/BLA (currently more than $3,200,000) and seven years of market exclusivity.
If the orphan indication is specific to pediatric patients, approval can be accompanied by the granting of a Rare Pediatric Disease Priority Review Voucher (PRV). These allow a company to request Priority Review of a submission to potentially accelerate FDA review and approval of a marketing application. Most PRVs have been sold at a price in excess of $100,000,000.
Recognition of the need for more studies to understand the safety and effectiveness of drugs in the pediatric population has led to an increased focus from the FDA and congress for clinical trials that include pediatric subjects.
Understanding the requirements and incentives for pediatric drug development are important for all drug developers. Ultimately, these efforts are designed to enhance the health and medical care of children.
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