Commenters push back on FDA’s plans for PREA compliance, pediatric exclusivity

Stakeholders responding to two draft guidances released by the US Food and Drug Administration’s (FDA) concerning exclusivity extensions for written request (WR) studies under the Pediatric Research Equity Act (PREA) have noted that the agency’s plans may reduce the overall number of pediatric studies being conducted and the number of WRs being sought for pediatric indications.

The Best Pharmaceuticals for Children Act (BPCA) can provide developers of novel pediatric drugs a six-month window of exclusivity before generic versions of the drugs could be brought to market if they fulfill the terms of a WR from the agency. The exclusivity period is in addition to other exclusivities and patents that apply to the product and is not conditional on positive study results or receiving a new indication. FDA may initiate the WR, or sponsors may request one from the agency by submitting a proposed pediatric study request (PPSR).

However, the recent draft guidance issued by FDA stated that the agency no longer plans to issue WRs “solely for studies or planned studies that are required under PREA.” (RELATED: Dual draft guidances outline FDA vision for pediatric drug development, exclusivity, Regulatory Focus 19 May 2023)

“PREA requirements have resulted in an increase in pediatric labeling, even without the added incentive of the BPCA,” the agency wrote in the guidance. “In light of the data on pediatric labeling changes pursuant to the BPCA and/or 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.”

A handful of stakeholders commented in response to both the “Pediatric Drug Development: Regulatory Considerations—Complying with the Pediatric Research Equity Act and Qualifying for Pediatric Exclusivity Under the Best Pharmaceuticals for Children Act” and “Pediatric Drug Development Under the Pediatric Research Equity Act and the Best Pharmaceuticals for Children Act: Scientific Considerations” draft guidances released in May 2023. While supportive of FDA’s efforts to update the agency’s 2005 guidance on PREA compliance, commenters took issue with several of FDA’s positions, including giving BPCA most of the credit for an increase in pediatric research, the limitations of pediatric exclusivity extensions for PREA and how these changes might negatively impact the development drugs for rare pediatric diseases.

Writing to the agency, Eli Lilly and Company noted it is the combination of BPCA and PREA that has resulted in an increase of pediatric studies over the last several decades, rather than PREA being “principally responsible,” as the agency asserted.

“We disagree not only with this characterization but also its premise, which assumes that it is possible to isolate the impact of either statute from the other during the timeframe when both BPCA and PREA have been in effect,” they wrote. “The two statutes complement each other, and their collective impact cannot be attributed to only one statute.”

Incentives in pediatric research

The Biotechnology Innovation Organization (BIO) told FDA that while BPCA and PREA “are intended to work together,” WRs were usually issued for PREA studies alone. The agency’s decision to no longer issue WRs based on only PREA studies “is a major change and is not justified based on data included in the guidance,” they said.

“If the Agency is requiring data under PREA, they must be doing this because they believe that the product may produce health benefits in the pediatric population – if the product did not have that potential, a waiver would be granted under PREA,” BIO explained. “The Agency should consider the chilling effect on limiting the use of BCPA to only studies that are above and beyond those required under PREA.”

The Pharmaceutical Research and Manufacturers of America (PhRMA) said no longer issuing WRs for PREA studies alone would be at odds with the conditional nature of BPCA’s statutory text that states WRs “may consist of a study or studies required under” PREA.

“In all, this proposed policy would be inconsistent with the statutory objective of trying to encourage sponsors to undertake pediatric studies. We urge FDA to reconsider this proposed policy and, at a minimum, to commit clearly and unambiguously that the Agency will not seek amendments of existing Written Requests consisting solely of PREA studies to align them with this proposed policy,” they wrote.

PhRMA also expressed concerns in their comment about FDA suggesting they can “change the conditions” around how a sponsor obtains pediatric exclusivity, “which would undermine incentives for conducting pediatric studies and discourage even seeking a Written Request as an initial matter.”

AbbVie noted in their comment to FDA that BPCA’s intent was to incentivize drug developers to conduct pediatric studies. “This policy interpretation, specifically the FDA practice of including pediatric studies in all relevant indications for a particular molecule in a single WR, presents a significant feasibility challenge for Sponsors,” they said.

“The policy approach in this draft guidance reverses the longstanding principle that PREA and BPCA work together to require and incentivize pediatric research, and will mean that Sponsors who develop their molecules in adults for all relevant indications (and conduct PREA-required studies for those indications) will have no opportunity to earn pediatric exclusivity,” they explained.

Orphan products

The National Organization for Rare Disorders (NORD) wrote that the agency’s new draft guidance would negatively impact development of drugs for rare diseases affecting children, noting that “developing therapies for rare diseases is uniquely challenging.”

NORD explained that while FDA’s shift from issuing WRs for studies under PREA alone “may be warranted in many cases,” the agency should reconsider this policy for orphan drugs under PREA. It is vital to have “the right mix of incentives” for rare disease drug development, NORD argued, and prioritizing orphan drug development in BPCA creates these incentives.

“By allowing BPCA to issue Written Requests (WR) to orphan products that fall under PREA requirements, drug sponsors of these orphan products will continue to have access to this important program to study pediatric labeling to determine safety, efficacy, and proper dosage,” they said. “This will help increase the number of orphan products that have complete pediatric labeling, which is vital to the safety of the pediatric population.”

PhRMA said that the draft guidance’s current language indicating the orphan exemption would not apply if FDA decided a drug met orphan drug status after an approval, which “does not align with the statutory text, which does not limit the orphan exemption based on when the orphan- drug designation is granted.”

“[T]he Agency should revise the guidance accordingly,” they wrote.

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Commenters push back on FDA’s plans for PREA compliance, pediatric exclusivity

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