As we have noted in this blog previously, under the Pediatric Research Equity Act (PREA), all new drug applications for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration are required to contain an assessment of the safety and effectiveness of the product for the claimed indication(s) in all relevant pediatric subpopulations unless this requirement in waived, deferred, or inapplicable. This includes products approved via the 505(b)(2) pathway. Given that a drug developer may want to obtain approval for adults first, it is common to request that the requirement for pediatric studies be deferred until after approval of the new drug application. We have also discussed previously the timing and process of gaining agreement from the Agency on the proposed Pediatric Study Plan under the Food and Drug Administration Safety and Innovation Act (FDASIA; also known as PDUFA V).

One important consideration involved in developing a PSP is the inclusion of specific age groups in the planned pediatric assessments. With sufficient support and justification, the FDA may grant a deferral or even partial waiver of pediatric studies in specific pediatric age groups. The 2005 Draft “Guidance for Industry: How to Comply with the Pediatric Research Equity Act” outlines the requirements for pediatric assessments in different age groups as follows:
The Best Pharmaceuticals for Children Act (BPCA) defines “pediatric studies” to include studies in all “pediatric age groups (including neonates in appropriate cases)” in which a drug is anticipated to be used (Section 505A(a) of the act). For 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. In general, however, the pediatric population includes patients age “birth to 16 years, including age groups often called neonates, infants, children, and adolescents” (21 CFR 201.57(f)(9)).

These age groups are also listed in the data standards manual for CDER Electronic submissions to define the age groups for which pediatric exclusivity may be requested (here). In this case, the Agency includes an “other age groups” category, leaving open the possibility of defining a unique age group for pediatric assessments based on reasonable justification. The February 2013 draft “Guidance for Industry and Review Staff: Pediatric Information Incorporated into Human Prescription Drug and Biological Products Labeling” takes this a step further stating that “the use of age categories depends on the indication and drug being studied and may be modified if there is a valid scientific rationale for an alternative approach (eg, Tanner staging).” Therefore, it is vital to the success of a pediatric development program to identify the most appropriate age groups for a given drug as well as any age groups for which that drug may not be safe or effective.

Recent experience and news in the pharmaceuticals world has highlighted the importance of identifying the most appropriate strategy for pediatric assessments, and that gaining agreement from the FDA is not always as straightforward as published literature may lead you to believe. Understanding the unique characteristics of each age group and how they relate to disease development, drug absorption, distribution, metabolism, and excretion (ADME), pharmacokinetics, and pharmacodynamic response are all key to the development of an appropriate, and ultimately successful, pediatric study plan.

Several examples come to mind when considering appropriate drug- or indication-specific age groups for a pediatric development program. Birth control drugs provide an obvious example of an opportunity to define a unique “age” group for pediatric assessments. These drugs may be granted a waiver of pediatric studies for pre-menarchal children because it simply does not make sense to treat a person who is not able to get pregnant with a drug intended to prevent pregnancy. This waiver is independent of a specific age because of the relatively high variability in the timing of reproductive maturation.

The logic for birth control drugs seems obvious; however, other examples may be less so. Take for example products that undergo first-pass metabolism by Cytochrome P450 enzymes in adults. Neonates do not have the same complement of CYP450 activity that children and adolescents have. In cases like this, it may be dangerous to administer a product to neonates due to their relatively lower metabolic capacity; whereas, children 2 years of age and older would be perfectly capable of metabolizing the drug.

The success of a pediatric development program depends on the Sponsor’s understanding of their drug, its formulation, and the specific developmental changes in pediatric patients that may impact its safety and efficacy. It is important to identify and evaluate the impact of as many of these key variables during the development of the pediatric plan to optimize the potential for success of that program. Premier Consulting does this by utilizing our extensive experience in leveraging information in the published scientific literature, in addition to our experience interacting with the FDA, to identify the most efficient and effective path forward for our clients.