Waivers and Deferrals Under the Pediatric Research Equity Act - Pharmaceutical Technology

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Waivers and Deferrals Under the Pediatric Research Equity Act
The authors explain waivers and deferrals for pediatric studies of drugs and biologics as provided by the Pediatric Research Equity Act of 2007.


Pharmaceutical Technology


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 FDA has provided some specific information in a draft guidance, that describes how to comply with PREA (1).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 Three criteria taken directly from PREA are listed in the draft guidance as a basis for FDA granting a waiver, either on their own initiative or at the request of the applicant as follows: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.


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