Seeking to accelerate pediatric drug development, FDA offers guidance on requirements of two pivotal laws

It’s been two decades since the passage of two pivotal laws which created a new foundation for pediatric clinical testing in the U.S., the Pediatric Research Equity Act (PREA) and the Best Pharmaceuticals for Children Act (BPCA). But while the requirements may be old, FDA apparently feels that companies are too often failing to meet its requirements – or are just failing to meet them efficiently. Now the agency has revised and expanded a guidance document from 2005 into two separate documents which may serve to help sponsors meet their pediatric testing obligations more easily.

Regulatory background and context

Historically, pharmaceutical companies have been hesitant to test the use of their drugs in pediatric populations due to potential ethical issues, liability concerns, and the populations’ relatively small market share. This has led to pediatric patients frequently being treated “off-label” with drugs approved for adult use, which can have harmful consequences since children may metabolize drugs much differently and experience different side effects.
This is a relatively large group of patients. Under 21 CFR 201.57 (c)(9)(iv), pediatric age is defined as “from birth to 16 years old, including age groups often called neonates, infants, children, and adolescents.”
To incentivize pediatric clinical research, Congress passed the Best Pharmaceuticals for Children Act (BPCA) in 2002 and the Pediatric Research Equity Act (PREA) in 2003. Both laws were subsequently reauthorized several times before being made permanent by the FDA Safety and Innovation Act (FDASIA) in 2012. While both PREA and BPCA are similar in their general aims to promote pediatric research, they accomplish their goals in substantially different ways.
Under the BPCA, the FDA provides companies with a powerful incentive to conduct pediatric studies: an additional six months of marketing exclusivity, during which time the FDA may not approve a generic version of the same drug. To qualify, the FDA must first issue a Written Request detailing that there is a need for pediatric studies to be conducted or the sponsor can use a proposed pediatric study request (PPSR).
Conversely, PREA requires companies requesting the approval of a new drug (including a new active ingredient, new indication, new dosage form/dosing regimen/route of administration to conduct an assessment of whether their drug would be used in children and, if so, provide data to support adequate information for the drug’s label about proper dosing and administration of the drug in pediatric patients. This requirement is more commonly known as a pediatric assessment.
In 2017, Congress passed the FDA Reauthorization Act (FDARA), which included a provision known as the Research to Accelerate Cures and Equity (RACE) for Children Act, which requires sponsors to assess efficacy of adult cancer treatments for children, regardless of the indication. The legislation removed the exemption for drugs with orphan drug designation put in effect under PREA, but only for cancer drugs. The RACE for Children Act enables the FDA to require a pediatric assessment when the treatment might be “germane to pediatric cancer,” affect a substantial number of children, or provide “a meaningful therapeutic benefit.”
Section 504 of FDARA/RACE requires sponsors to conduct these studies based on the molecule’s mechanism of action, and not just on clinical indication, a move meant to facilitate more studies in cancers for which the molecular target is similar in both adult and pediatric patients.
Since the passage of FDARA, the FDA has been busy developing and releasing guidance documents intended to provide industry with new details about the operation of the new requirements. In May 2021, the FDA finalized its 2019 draft guidance on the implementation of FDARA for Pediatric Studies of Molecularly Targeted Oncology Drugs. [ Read our analysis of the final guidance document here.] FDA has also finalized a guidance document on the submission of iPSPs and how to request waivers or referrals. [ Read our analysis of that guidance document here.]
To help companies comply with pediatric research requirements, the FDA has issued numerous guidance documents over the years. For example, in recent years it has released guidance on measuring growth and evaluating pubertal development in pediatric clinical trials; on ethical considerations for clinical investigations of medical products involving children; on general clinical pharmacology considerations for pediatric studies of drugs and biologics; on pediatric extrapolation; on considerations for long-term clinical neurodevelopmental safety studies in neonatal product development; on the development of anti-infective drug products for the pediatric population; on requirements for molecularly-targeted oncology drugs for pediatric studies; on nonclinical safety testing in support of the development of pediatric drugs; on pediatric study plans; on cancer clinical trial eligibility criteria and minimum age considerations; and the development of anti-infective drug products for the pediatric population.
However, the FDA has published relatively few guidance documents solely focused on PREA. In fact, a review of the FDA’s guidance document database revealed just one document: A 21-page draft guidance document from 2005 focused on how to comply with PREA.

What’s new

Now the agency is revising and expanding upon that guidance in a major way, unveiling two documents that focus on scientific considerations for pediatric development under PREA and on the BPCA, and qualifying for PREA exclusivity, that will together serve to replace the earlier guidance.
Make no mistake: FDA’s two new guidance documents are for the most part relatively high-level documents. For example, the 19-page guidance on scientific considerations for pediatric drug development under PREA spends the first 9 pages on an overview of the legislative framework for pediatric drug development and some of the agency’s internal processes for handling these applications, such as its internal pediatric review committee, the PeRC, which handles all iPSPs, waivers, deferrals, assessments, extensions and written requests.”
Because these guidance documents are, combined, more than 60 pages, we’re just going to highlight some of the most important parts in this analysis.

FDA’s new guidance on scientific considerations under PREA

For persons already familiar with developing pediatric products, much of the scientific considerations guidance will be fairly obvious. The guidance explains the purpose of pediatric study plans (“to identify needed pediatric studies early in drug development and begin planning for these studies”) and general principles of pediatric development (“applications should consider whether efficacy could be partially or fully extrapolated from studies in adults or other pediatric populations”).
There are a few elements of the guidance that are somewhat interesting, even if intuitive. For example, the guidance explains that a pediatric dosage form needs to be specially formulated for its targeted age group (or groups), including the volume and size of the dosage form, its palatability, whether it will be chewed or swallowed (or mixed in with foods), and whether any device is needed to administer it.
And while nonclinical data may be helpful for supporting the initiation of studies in pediatric populations, “such studies may not always assess possible drug effects on developmental processes that occur at specific ages in pediatric populations,” the guidance notes. Companies should therefore consider juvenile animal studies (both in vitro and in vivo) to assess particular hazards, although FDA advises that sponsors discuss such approaches prior to initiating the studies.
The timing of pediatric studies for life-threatening diseases: Another interesting addendum in the guidance is that pediatric studies for life-threatening diseases for which approved treatment is not available “should be considered earlier in development than might occur for less serious diseases.” For certain drugs, this may occur as early as phase one of clinical testing, or as soon as initial safety data in adult subjects are available. However, availability will depend on safety data in adults, and that such data demonstrate a “sufficiently low risk of the intervention or procedure or that the prospect of direct benefit to the enrolled pediatric populations is sufficient to justify the risks.” In cases where companies feel they need to first obtain adult safety and efficacy data, or where the prospect of direct benefit is less clear, companies may request a deferral of required pediatric studies. “However, if substantial pediatric use may be anticipated after the drug is approved for use in adults, early initiation of pediatric studies should be considered,” FDA explained.
On neonates: FDA has previously authored guidance on the topic of the development of drugs for the neonatal population, defined as the age of 0 days through 27 days of corrected gestational age. Due to the extremely short duration of this “age,” it is phenomenally difficult to conduct testing in this population (to say nothing of inherent ethical issues and parental reluctance). The guidance notes that the FDA may require that pediatric tests include neonates, but that it may also waive these requirements. However, when conducting a pediatric assessment under PREA, “applicants are required to submit assessments that are adequate to assess safety and effectiveness for the claimed indications in all relevant pediatric age groups, which may include neonates,” the guidance explains.

FDA’s second guidance, on qualifying for pediatric exclusivity under the BPCA and complying with PREA, is similarly written at a high level

The 43-page draft guidance also contains extensive backgrounds on PREA and the BPCA, and generally providers sponsors with a detailed walk-through of their obligations under federal law and the FDA’s processes. However, there are also a few points of advice that are somewhat more targeted and helpful for sponsors who may already be familiar with the requirements of PREA and the BPCA.
For example, for sponsors developing drugs for life-threatening or severely debilitating conditions and unmet medical needs, FDA says it encourages companies to “discuss the pediatric plan at pre-investigational new drug application (pre-IND) and end-of-phase 1 meetings” – or even earlier, if data are available or if the condition or disease “primarily or substantially occur[s] in the pediatric population.”
It’s worth noting as well that PREA requirements to conduct pediatric testing generally do not apply to products intended to treat rare diseases for which Orphan Drug Designation has been granted. However, there are instance in which this exception does not apply – for instance, if a product has already been approved for a non-orphan indication, or if the drug is related to pediatric oncology under the RACE for Children Act. As FDA notes, “The PREA orphan exemption is not revisited to retroactively abrogate a PREA requirement that was properly imposed before orphan designation was granted.” However, even if drugs are exempted from the requirements for testing, the FDA may still issue a Written Request that may be accepted by the sponsor on a voluntary basis.
Pediatric formulations: As the FDA notes, sponsors need to conduct pediatric studies “using appropriate formulations for each age group.” However, this sometimes isn’t feasible due to development challenges. In such cases, sponsors may seek – and FDA may grant – a partial waiver. In addition, companies are required to submit a “request for approval of a pediatric formulation” used in their pediatric studies, and failure to do so could result in a drug being considered misbranded. FDA recommends that sponsors “begin the development of an age-appropriate formulation as early as possible” to avoid unnecessary delays.
Waivers and deferrals: The guidance does contain extensive information on a topic that is likely to be of interest to many pharmaceutical and biopharmaceutical companies: How can they avoid doing certain requires tests in cases where they feel it would be unwarranted? The guidance contains an explanation of how sponsors may receive a full or partial waiver, as well as deferrals. While much of this information is a straightforward reflection of the statutory requirements listed in the PREA legislation, it’s still helpful to have all of the criteria in a single place. It is also augmented by specific timeline recommendations (i.e., when to submit these requests), what to include in a request, and the information FDA plans to take into account when making its decision.
Sponsors familiar with the BPCA in general may benefit from the guidance document’s detailed explanation of FDA’s processes. For example, the guidance contains more than a dozen pages of detail about Written Requests (WRs), what they may contain (such as requests for nonclinical studies), FDA’s process for amending WRs (including at the request of a sponsor), how to obtain a WR, the submission of a Proposed Pediatric Study Request (PPSR), and a sponsor’s acceptance of a WR.

What’s next

As a general rule, when the FDA releases a guidance document, it’s meant to solve one of two problems: Either companies are asking the FDA for additional guidance to provide assurance for their favored development approaches, or the FDA is seeing so many problems with companies doing things wrong that it feels compelled to step in to address those problems. These guidance documents seem to be focused on the latter problem. Neither PREA nor the BPCA are recent pieces of legislation – they’ve been around for two decades, and most companies have at least some experience with pediatric testing requirements. For the FDA to now be releasing new guidance on these subjects seems to us to be an indication that companies are repeatedly asking the FDA the same basic questions, and that this guidance is an attempt to preemptively answer some of them, or to reduce the chances that companies will pursue an inefficient development approach. As FDA notes in its PREA/BPCA guidance, “many sponsors conduct their entire clinical programs in other countries and occasionally submit a marketing application with little, if any, prior interaction with FDA. All sponsors who seek to market their drugs in the U.S. are strongly encouraged to contact FDA as early as possible to avoid any delay in providing any required pediatric information in their applications.”
As explained in a statement, it also appears that FDA is primarily interested in reducing the lag time between when a drug is made available to adult and when it is subsequently made available to pediatric populations. “FDA is committed to reducing the substantial lag between approval of a drug for adult use and the approval in children,” said Lynne Yao, director of the Division of Pediatrics and Maternal Health. “These two documents provide the agency’s current thinking about how industry can comply with PREA and BPCA and, ultimately, help increase the availability and timeliness of safe and effective medicines and vaccines for children in the U.S.”

To contact the author of this analysis, please email Alec Gaffney ( agaffney@agencyiq.com)
To contact the editor of this analysis, please email Kari Oakes ( koakes@agencyiq.com)