New FDA pediatric draft guidances include proposal that could limit pediatric exclusivity grants

FDA’s pediatric framework consists of a “carrot” and a “stick,” where the Best Pharmaceuticals for Children Act (BPCA) offers exclusivity for certain pediatric studies, while the Pediatric Research Equity Act (PREA) mandates pediatric studies for certain pharmaceuticals and biologics. Under the BPCA, which was originally enacted in 2002 and codified at section 505A of the Federal Food, Drug, and Cosmetic Act (FDCA), drug and biologics sponsors are awarded a six-month period of pediatric exclusivity that extends other patents and regulatory exclusivities in exchange for conducting pediatric studies in accordance with a written request (WR). On the other hand, PREA, enacted in 2003 and codified at section 505B of the FDCA, generally requires sponsors of new active ingredients, indications, dosage forms, dosing regimens, or routes of administration to conduct pediatric assessments, unless such assessments are waived or deferred by FDA. Together, the BPCA and PREA provide incentives and requirements to spur study in pediatric patients so that drugs and biologics can be labeled with useful information for children.

Although both BPCA and PREA have been in existence for decades and play critical roles in drug development, FDA has published little comprehensive guidance about the two programs. In 1999, prior to enactment of the BPCA, FDA published a guidance entitled “Qualifying for Pediatric Exclusivity Under Section 505A of the Federal Food, Drug, and Cosmetic Act,” which provided insight into the process for obtaining pediatric exclusivity and its scope. The guidance was subsequently withdrawn and, since its withdrawal, FDA had not provided official guidance regarding pediatric exclusivity -- until now. With respect to PREA, FDA had issued a draft guidance in 2005 entitled “How to Comply with the Pediatric Research Equity Act” and more recently issued a few guidances on certain specific PREA-related questions. Once finalized, the two new draft guidance documents will replace the 2005 PREA draft guidance.

Regulatory Considerations draft guidance

The new draft guidance, “Pediatric Drug Development: Regulatory Considerations — Complying With the Pediatric Research Equity Act and Qualifying for Pediatric Exclusivity Under the Best Pharmaceuticals for Children Act,” provides a comprehensive overview of how sponsors can comply with PREA and qualify for pediatric exclusivity. The draft guidance explains what is required under PREA, who is subject to PREA requirements, and how to conduct the required pediatric studies or receive a waiver or deferral. Regarding pediatric exclusivity, the draft guidance explains that a sponsor must be in receipt of a WR from FDA to qualify for exclusivity, how FDA determines whether studies “fairly respond” to the WR such that exclusivity would be granted, and the scope of the exclusivity once granted (i.e., the patents and exclusivities upon which pediatric exclusivity attaches).

FDA’s proposed new policy on WRs

Most notably, the regulatory considerations draft guidance includes a proposed change in policy that would limit the issuance of WRs. Specifically, the draft guidance says that, upon finalization, WRs will be reserved only for sponsors who conduct additional pediatric studies beyond what is required under PREA:

FDA believes WRs should be reserved for those sponsors who conduct additional pediatric studies — beyond what is required under PREA — that may produce health benefits in children. Thus, upon finalization of this guidance, FDA does not expect to issue WRs solely for studies or planned studies that are required under PREA. In general, FDA expects that a WR that includes studies or planned studies required under PREA will also include additional indications or populations. If there are no additional studies for indications or populations that may produce health benefits in the pediatric population beyond the studies or planned studies required under PREA, then FDA does not expect to issue a WR for that drug.

If the draft guidance is finalized, this new policy would represent a change from FDA’s historic practice under which a sponsor could benefit from pediatric exclusivity even though it was doing solely what was already required under PREA. The draft guidance explains that the scope of studies FDA has authority to request under a WR is much broader than what it can require under PREA, so this new proposed policy could potentially lead to more expansive WRs when issued for sponsors with existing PREA obligations.

What does “fairly respond” to a WR mean for exclusivity eligibility purposes and when does pediatric exclusivity attach to subsequent applications?

Other notable sections in the regulatory considerations draft guidance discuss how FDA determines whether studies “fairly respond” to a WR and how pediatric exclusivity will apply to applications submitted after pediatric exclusivity is obtained.

In the discussion on how FDA assesses whether studies “fairly respond” to a WR, FDA explains that its pediatric exclusivity boards analyze whether the studies were designed and conducted by the sponsor in a way likely to meet the objectives specified in the WR and underlying the exclusivity provision as a whole. When a sponsor meets the terms of the WR, studies are determined to be a fair response because they were conducted in accordance with the trial’s plans and objectives, regardless of whether meaningful pediatric information was produced. Even when a sponsor does not meet the terms of the WR, a fair response is possible if, considering the data provided by the sponsor as a whole, the sponsor meets the objectives of the WR by generating clinically meaningful information of the general type the WR contemplates.

Regarding subsequent applications containing the same active moiety for which a sponsor previously qualified for pediatric exclusivity, FDA states that “pediatric exclusivity does not attach to new (not previously listed) patents or exclusivity covering the later filed applications or supplements unless the subsequent drug product could not be labeled without the data that qualified the previously approved drug product for the prior pediatric exclusivity.” FDA also notes that if pediatric exclusivity has attached to a listed patent or exclusivity protecting the previously approved application that also protects a new application held by the same sponsor, the pediatric exclusivity also attaches to that same patent or exclusivity in conjunction with the new application.

Scientific Considerations draft guidance

The other new draft guidance, “Pediatric Drug Development Under the Pediatric Research Equity Act and the Best Pharmaceuticals for Children Act: Scientific Considerations,” aims to assist industry in developing data and obtaining information needed to support approval of drug products in pediatric populations. This draft guidance discusses scientific considerations relevant to the overall strategy of a pediatric drug development program; however, it generally emphasizes how “the principles that guide pediatric drug development do not differ greatly from the principles that apply to drugs developed for adults.” Among other things, the draft guidance explains that FDA may determine that pediatric effectiveness can be extrapolated from adequate and well-controlled studies in adults in certain circumstances, when pediatric studies should be initiated relative to adult studies, and specific considerations for drug development in neonates.

Outstanding issue and opportunity for public comment

Omitted from both draft guidances is explanation of how FDA decides which indications or studies it will include in a WR. In the past, the agency has included studies on multiple indications, and it remains unclear how FDA determines which indications meet the standard of potentially producing health benefits and what studies sponsors can anticipate when seeking pediatric exclusivity. This issue may become more prevalent because of FDA’s proposed change in policy regarding issuing WRs only for studies going beyond what is required under PREA.

There is an opportunity for public comment regarding the two draft guidance documents, and FDA has requested that comments be submitted by July 17. If you wish to submit a comment, or have any questions on pediatric drug development and exclusivity in the U.S., you may contact any of the authors of this alert or the Hogan Lovells attorney with whom you regularly work.

Authored by Gary Veron, Deborah Cho, and Bryan Walsh