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PREA and Fixed-Dose Combinations: When Things Get Complicated

The Pediatric Research Equity Act (PREA) was signed into law in 2003 to increase pediatric use information in product labeling and close knowledge gaps regarding the safety, efficacy, and appropriate dosing of drugs to treat children. PREA requires new drug applications (NDAs) and biologics license applications (BLAs) for a new active ingredient, indication, dosage form, dosing regimen, or route of administration to contain a pediatric assessment, unless the applicant obtains a waiver or deferral of pediatric investigations (for example, when the disease rarely or never occurs in children or when orphan designation has been granted). In practice, this means sponsors must conduct studies in children prior to marketing authorization, unless they have a rationale to defer or waive them.

This blog post will explore PREA’s implications for developing oncology fixed-dose combination (FDC) products and some key considerations for addressing difficult regulatory questions.

Pediatric requirements for molecularly targeted cancer products

Originally, PREA targeted only those products developed for diseases and/or conditions that occur in both adult and pediatric populations. However, the FDA Reauthorization Act of 2017 (FDARA) amended PREA to require timely pediatric investigations of certain new active ingredients intended for the treatment of adult cancers, even if the indication does not occur in children and/or orphan designation has been granted. These investigations are based on the molecular target of the product, rather than on the disease or condition.

Since FDARA was implemented, the FDA has published and maintained a list of molecular targets that the agency considers substantially relevant to the growth or progression of a pediatric cancer and which require molecularly targeted pediatric cancer investigations (unless waived or deferred). This is called the Relevant Molecular Target List (Relevant List). Molecular targets that are not considered substantially relevant to the growth or progression of pediatric cancers, and which therefore warrant a waiver of PREA’s requirements, are recorded on a second list called the Non-Relevant Molecular Target Leading to Waiver List (Non-Relevant List).

These lists are intended to provide guidance in planning for initial pediatric study plan (PSP) submissions for new oncology products in development. However, the fact that a drug is directed at a molecular target on the Relevant List does not necessarily mean that pediatric cancer investigation reports must be submitted. In the same way, the absence of the molecular target from the Relevant List does not necessarily mean that submission of such reports is not required. Thus, reaching out to the FDA to discuss a pediatric plan is crucial.

Complying with PREA when developing a fixed-dose combination product

FDC products, which consist of two or more drugs combined in a single dosage form, are subject to PREA. However, because each program is unique, early discussions with the agency are essential to delineate an adequate and feasible pediatric assessment plan. This is especially true in unusual situations, which can often emerge during the development of FDC products.

When conducting a PREA evaluation for an oncology FDC product, a sponsor may find it simpler to focus on the proposed indication, rather than on the molecular target(s). For example, an FDC product may be indicated for a condition that is included in the FDA’s automatic waiver list (Adult-Related Conditions that qualify for a waiver because they rarely occur in pediatrics) and for which the molecular target is irrelevant for pediatric conditions.

Alternately, PREA evaluations for oncology FDCs may be based on their molecular mechanism of action rather than clinical indication. If an FDC targets a molecule included in the Relevant List, molecularly targeted pediatric cancer investigations will likely be required. However, which pediatric studies will be required, and whether they can be deferred until safety data in adults is collected, will depend on the sum of available evidence (both public and from the sponsor) on the safety of the product in children.

When an FDC does not target any molecules on the Relevant List, a deferral of pediatric studies until safety data in adults is collected is usually an option. If the molecular target(s) are on the Non-Relevant List, a waiver of molecularly targeted pediatric cancer investigations could be warranted, if it is well-justified by scientific evidence.

When things get complicated

An FDC may contain one or more active ingredient for which the molecular target is present on the Relevant List, plus one or more active ingredient for which the molecular target is not present on the Relevant List or is present on the Non-Relevant List. How is PREA compliance handled in this case? As with most regulatory questions, the answer is, “It depends.”

A sponsor may request a waiver of pediatric studies for a proposed FDC if there is scientific evidence strongly suggesting that one or more components of the FDC is unsafe in pediatric patients. A waiver may also be an option if the FDC is not likely to be used in a substantial number of pediatric patients.

But what if the active ingredient(s) on the Relevant List targets a condition that is not extremely rare in children or may represent a meaningful therapeutic benefit over existing therapies? While a deferral until additional safety or effectiveness data have been collected may be appropriate, important questions could arise that need to be addressed, such as:

  • If not all active ingredients are deemed relevant for pediatric cancers, would evaluating the FDC in pediatric patients expose them to the non-relevant active ingredient(s) needlessly?
  • Does the benefit of treating the pediatric patients with the relevant component(s) of the FDC outweigh the risk of exposing them to the other component(s), which do not offer any benefit and may even induce adverse events?
  • Will the sponsor be required to prepare a new formulation containing only the relevant active component(s) of the FDC to be evaluated in pediatric studies?

A sponsor should consider these points when formally submitting the required PSP to the FDA and include questions designed to gain clarification and agreement from the agency on the best way to proceed. However, it is important to remember that, according to the FDA’s current thinking, children should only participate in clinical trials when their participation is needed to further the scientific understanding of a product’s use in children. The risk for interventions or procedures with a “prospect of direct benefit” must be assessed to justify exposing children to investigational products in clinical trials.

In Premier Consulting’s extensive experience with pediatric plans, interactions with the FDA — especially those led by regulatory experts — are key to fully understanding the best path to follow while developing products intended to be marketed in the U.S. Establishing requirements for pediatric studies early in a development program allows for flexibility is complying with PREA, so that pediatric subjects can be included in a sponsor’s planned studies or separate studies can be incorporated into a program as soon as possible.


Vanessa Atayde, PhD
Senior Associate, Regulatory Affairs