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Is Your Drug Eligible for a Pediatric Waiver or Deferral?

Is Your Drug Eligible for a Pediatric Waiver or Deferral?
02 April 2019

To improve the availability and quality of pediatric medicines for children, the FDA has implemented two key pieces of legislation through Congress: the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA). This legislation has provided both mandates and incentives for companies to formally engage in pediatric drug development. 

Pediatric drug development has been a highly-neglected area for decades. Some results include the widespread “off-label” use of drugs in children and the undesirable practice of “extemporaneous re-formulation” of adult products for pediatric use.

Since the implementation of PREA in 2014, a formal process of pediatric drug evaluation and development is now required at the end of Phase II studies in the U.S. The implications of PREA have been far-reaching for drug companies involved in new product development, with mandates in place to evaluate and develop drugs across a broad array of therapeutic areas and diseases that may be applicable to children.

However, there are some notable exceptions to this process where a pediatric assessment may be unnecessary, undesirable, impractical, or delayed. Indeed, the legislation authorizes the FDA to grant waivers under certain circumstances for example if a) the disease is not encountered in the pediatric population, b) there is little or no perceived value in children with a certain disease or condition, and c) the drug may pose an unacceptable risk to the child. 

Situations may also arise where pediatric development is required but certain critical information, on for example drug safety or drug exposure in adults, is missing or if certain non-clinical toxicology or formulation studies may still need to be conducted.  Under these situations, it may be possible to negotiate a deferral with the agency until this information becomes available. The following summary provides a high-level overview of the pediatric waiver and deferral process in the U.S. and how Synteract works with clients to establish the best regulatory path to follow when developing an initial pediatric study plan (iPSP).   

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 Three criteria taken directly from PREA are listed in the draft guidance as a basis for the FDA granting a waiver, either on their own initiative or at the request of the applicant, as follows:

  • Necessary studies are impossible or highly impractical (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)).

Partial waivers. 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)).

Deferrals.  As implied by the name, a deferral delays the submission of the pediatric assessment rather than eliminates 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.

At Synteract, we draw on extensive experience in pediatric clinical trials, including leveraging emerging strategies in pharmacokinetics and PK/PD, to help sponsors to develop the most appropriate configurations for their studies. We critically look at the background and available information on each program to provide specific guidance on the best regulatory path to take and when it is appropriate to consider a waiver or deferral as part of the pediatric strategy.

Contact us to discuss how we can help bring your pediatric clinical trials to life.

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