Waivers and Deferrals Under the Pediatric Research Equity Act

The Pediatric Research Equity Act of 2007 (PREA), enacted as Title IV of the Food and Drug Administration Amendments Act of 2007 (FDAAA), authorizes the US Food and Drug Administration to require pediatric studies of drugs or biologics that are likely to be used in a substantial number of children or would provide meaningful benefit over existing treatments for children. A consequence of this Act is that all new drug applications (NDAs) must address pediatric assessment. However, not all NDAs require that pediatric clinical studies be done, or that they be done before NDA approval. The challenge for drug-development companies is to determine when and how they can avoid unnecessary clinical studies and delays to drug approval.

Waivers and deferrals

PREA recognizes that, under some circumstances, pediatric assessment may be unnecessary, undesirable, impractical, or delayed, and so the legislation authorizes FDA to grant waivers or deferrals to the pediatric assessments required under the Act. If the applicant requests a waiver or deferral, either full or partial, appropriate and sufficient supporting evidence must be provided. The criteria for granting waivers or deferrals center on safety, the nature of the drug product, and the practicability of the requisite studies. FDA has provided some specific information in a draft guidance, that describes how to comply with PREA (1).

Full waivers. Under a waiver, the pediatric assessment does not have to be completed. Three criteria taken directly from PREA are listed in the draft guidance as a basis for FDA granting a waiver, either on their own initiative or at the request of the applicant as follows:

• Necessary studies are impossible or highly impracticable (Federal Food, Drug and Cosmetic Act (FD&C), as amended by PREA, Section 505B(a)(4)(A)(i))
• There is evidence strongly suggesting that the drug or biologic product would be ineffective or unsafe in all pediatric age groups (FD&C, as amended by PREA, Section 505B(a)(4)(A)(ii))
• 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)).

Necessary studies are impossible or highly impracticable (FD&C, as amended by PREA, Section 505B(a)(4)(A)(i)). Under this provision, FDA provides some general examples of the type of situations where it would be likely to grant a waiver. These are:

• The number of subjects is very small
• The patients are "geographically dispersed" and
• The product's indication has "extremely limited applicability to pediatric patients because the pathophysiology or disease occurs for the most part in adult populations."

There does not appear to be much difference between the first two examples; either would probably involve a product which was at or below orphan-drug levels with regard to pediatric use. The third example likely represents the most readily available type of waiver situation (i.e., one in which the product and indication are aimed at a disease or affliction occurring primarily in the adult population, making a pediatric assessment moot). For this example, the FDA guidance provides a list of 20 specific diseases such as Alzheimer's, arteriosclerosis, menopause symptoms, and 12 types of cancer that presumably would qualify for a waiver. The list appears on a sample waiver request and includes, in addition to the 20 specified diseases, an "other" option that includes the instruction, "please state and justify." Thus, while providing a list of specific candidates for a waiver, the FDA presumably leaves the door open for other products and indications to be accepted as essentially limited to adults, provided the sponsor can make that case convincingly.

There is evidence strongly suggesting that the drug or biologic product would be ineffective or unsafe in all pediatric age groups (FD&C, as amended by PREA, Section 505B(a)(4)(A)(ii)). In this situation the FDA's guidance does not provide any examples, so the applicant would have to assemble the evidence regarding the specifics for the product or disease in question. It's unlikely that the applicant would have actually run studies in this regard, but if so, they would go directly to support of the waiver. More often, studies in the published literature could provide the evidence necessary to support a waiver under this requirement. Also, the Act requires that, if a waiver is granted under this section, the product labeling must include the information supporting the waiver.

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 definition.

Partial waiver

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.

Deferrals

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, Section 505B(a)(3)(A)(ii)).
• 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"

References

1. FDA, Guidance for Industry: How to Comply with the Pediatric Research Equity Act (Rockville, MD, 2005), www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM077855.pdf.

2. FDA, Premarket Assessment of Pediatric Medical Devices (Rockville, MD 2004), www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm089740.htm.