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 (FD&C, as amended by PREA, Section 505B(a)(4)(A)(iii))
. This section provides a waiver for a product that is a variation on already existing therapies. The guidance notes a number
of ways that a new product could provide a meaningful therapeutic benefit, but does not provide any examples of one that would
not. A possible example would be if there were already a product or products available in a solution or suspension, and an
applicant developed a comparable product in a solid dosage form, then the solid form could qualify for a waiver under this
section. The solid form would not represent a meaningful therapeutic benefit over the existing therapies, and the likelihood
of a substantial number of pediatric patients using the product should be low because pediatric patients commonly use liquid
medications. Substantiating the second part of the requirement could be challenging in some cases. In the guidance, FDA points
out that the Act does not define "substantial number," but cites prior FDA consideration of 50,000 patients as meeting the
The Act also provides for the grant of a partial waiver for specific pediatric age groups. The FDA guidance generally defines
the pediatric population as "birth to 16 years, including age groups often called neonates, infants, children and adolescents"
(21 CFR 201.57(f)(9)). No actual age ranges are provided, though suggestions have been provided in other documents (2). The guidance
states: "For the purposes of satisfying the requirements of PREA, the appropriate age ranges to be studied may vary, depending
on the pharmacology of the drug or biological product, the manifestations of the disease in various age groups, and the ability
to measure the response to therapy." This provision means that the drug developer is required to make the case that not all
pediatric age groups need to be studied, although some should be.
The guidance supplies the same three criteria for a partial waiver as for full waiver, and adds a fourth requirement as follows:
The applicant can demonstrate that reasonable attempts to produce a pediatric formulation for that age group have failed
(FD&C, as amended by PREA, Section 505B(a)(4)(B)(iv)).
In the guidance, FDA discusses the likelihood that the physiological differences and dosing requirements for pediatric patients,
especially the very young, will often require one or more separate pediatric formulations. This partial waiver provision acknowledges
the possibility that workable formulations may not always be possible. For example, a pediatric formulation that avoided the
use of a potentially problematic excipient might result in a product that was unstable. If no acceptable substitute excipient
were available, a waiver for the affected age group could be granted.
Overall, unless the applicant can make a case for a waiver under the first provision (demonstrating that the product is simply
not applicable to children), obtaining a waiver can be difficult.
As implied by the name, a deferral delays the submission of the pediatric assessment rather than eliminating it. The Act allows
for delay in submitting the pediatric assessment until after the NDA has been submitted, or even until a specific date after
approval of the NDA (FD&C, as amended by PREA, Section 505B(a)(3)). FDA is often receptive to this.
Three criteria for a deferral are available as follows:
The drug or biological product is ready for approval for its use in adults before pediatric studies are complete (FD&C, as
amended by PREA, Section 505B(a)(3)(A)(i)).
Pediatric studies should be delayed until additional safety or efficacy data have been collected (FD&C, as amended by PREA,
- There is another appropriate reason for the deferral (FD&C, as amended by PREA, Section 505B(a)(3)(A)(iii)). For this deferral,
the guidance cites technical difficulties with a pediatric formulation as an example.
The guidance supplies an appendix which provides a suggested format and content for a deferral request. Also provided is a
list of factors the FDA will use in making its case-by-case determinations on deferrals as follows:
- The need for the drug or biologic in pediatric patients.
- Availability of sufficient safety data to initiate pediatric trials.
- The nature and extent of pediatric data to support pediatric labeling.
- The existence of substantiated difficulties in enrolling patients.
- Evidence of technical problems in developing pediatric formulations.
The bar for reaching agreement with FDA regarding a deferral appears relatively low. This provision makes sense because the
issue is not if the studies will be performed, but when.
Kathryn Wekselman, PhD and RN, is a senior director of research services, and William P. Stoltman, JD, is senior director of regulatory affairs and quality assurance, both with Camargo Pharmaceutical Services. Peter Joiner is CEO of Madeira Therapeutics.
For more on this topic, see "Pediatric Formulations: Technical and Regulatory Considerations" or see the online exclusive, "European Requirements for Pediatric Formulations"
1. FDA, Guidance for Industry: How to Comply with the Pediatric Research Equity Act (Rockville, MD, 2005),
2. FDA, Premarket Assessment of Pediatric Medical Devices (Rockville, MD 2004),