On May 17, 2023, FDA published two significant draft guidances addressing key pediatric drug development issues.[1] These long-awaited draft guidances outline FDA’s approach to administering the two statutes governing the development of pediatric data by drug sponsors: the Pediatric Research Equity Act (PREA), under which FDA requires sponsors to conduct certain pediatric studies; and the Best Pharmaceuticals for Children Act (BPCA), which provides the pediatric exclusivity incentive for sponsors to conduct pediatric studies of drug products. Together, the new draft guidances replace a draft guidance on PREA compliance that FDA issued in 2005.[2]
FDA’s two new draft guidances touch on many of the regulatory and scientific issues that sponsors confront when designing and executing pediatric drug development programs, though they each only “briefly” address the new molecularly targeted pediatric cancer investigation requirement added by the FDA Reauthorization Act (FDARA) in 2017. Many of the policies discussed in the two draft guidances generally align with previous Agency guidance and practice, but the draft guidances do articulate new approaches on some aspects of PREA compliance and pediatric exclusivity determinations. For example, FDA proposes a new policy under which the Agency would no longer issue Written Requests (WRs) (and grant pediatric exclusivity) solely for studies required under PREA, if this policy is retained in the final guidance.
This alert discusses highlights from the two draft guidances. The comment period for both draft guidances will close on July 17, 2023.
“Pediatric Drug Development: Regulatory Considerations—Complying With the Pediatric Research Equity Act and Qualifying for Pediatric Exclusivity Under the Best Pharmaceuticals for Children Act”
This 39-page draft guidance covers legal, regulatory, and procedural topics related to complying with PREA and qualifying for pediatric exclusivity under the BPCA. FDA addresses each statute in turn in the draft guidance, and the discussion includes positions not previously advanced in Agency guidance. The draft guidance does not, however, address in depth several key issues, including how FDA plans to interpret and apply section 505B(b) of the FDCA (which governs PREA study requirements for marketed drugs) and how pediatric exclusivity applies to combination drugs. The draft guidance also only briefly discusses how pediatric exclusivity applies to biological products.
Complying with PREA
The draft guidance addresses some core aspects of complying with PREA, such as submitting a pediatric study plan on the planned assessments, developing a pediatric formulation, and obtaining a waiver or deferral of a PREA requirement. FDA has covered these topics in other guidances, to an extent, including in the 2005 guidance that the two new draft guidances replace, but the draft guidance contains some new content. The following bullet points illustrate some of the key principles articulated in the draft guidance:
- The draft guidance states that, “[i]n general, sponsors should include pediatric studies at the time of submission of an application when there is sufficient knowledge to proceed and it is feasible to complete studies in children in parallel with adult studies.”
- According to the draft guidance, a partial PREA waiver based on a sponsor’s inability to develop a pediatric formulation may be granted if “the applicant can demonstrate that unusually difficult technological problems prevented it from developing a pediatric formulation.”
- In discussing deferral extension requests, FDA states “in general, FDA considers whether the applicant could have prevented or foreseen the delay.”
- The draft guidance notes that FDA may, “as appropriate,” issue a refusal to file or complete response letter if the applicant fails to comply with PREA.
Qualifying for Pediatric Exclusivity
The draft guidance also features a lengthy discussion about qualifying for pediatric exclusivity under the BPCA. This discussion walks through key aspects of the statutory process for earning pediatric exclusivity, which requires FDA’s issuance of a WR for pediatric studies (either on the Agency’s own initiative or in response to a proposed pediatric study request submitted by a sponsor). In addition to covering basic points about this process, FDA also generally describes how it assesses whether to issue a WR and, once a sponsor has submitted study reports pursuant to a WR, whether to grant pediatric exclusivity. For example:
- The draft guidance announces a new FDA position on the issuance of WRs. Per FDA, “[i]n 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. 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 particular, FDA asserts that “data [on pediatric labeling] suggest that studies required under PREA are successfully completed, and that PREA requirements have resulted in an increase in pediatric labeling, even without the added incentive of [pediatric exclusivity].”
- The draft guidance identifies factors FDA will consider in determining whether to award pediatric exclusivity. These factors are: (1) “[t]he purpose of the pediatric exclusivity provision as described in the statute, with reference to the legislative history,” which FDA says “makes clear that its purpose is to generate meaningful clinical information on the use of drug products in children that will result in a health benefit to pediatric populations”; (2) “[w]hether the sponsor met the terms of a WR”; and (3) “[t]he information sought in the WR and the objectives stated in the WR.” In its explanation of this approach, FDA suggests a sponsor may earn pediatric exclusivity even if its pediatric studies do not meet the terms of a WR, as long as the Agency determines that the “objectives” of the WR were met. The draft guidance also states that “[w]hen a sponsor meets the terms of a WR, the resulting studies fairly respond to the WR because studies that are carried out in accordance with the trial’s plans and objectives, as expressed in the WR, generally satisfy the statutory goal of obtaining meaningful pediatric use information.”
- FDA confirms that pediatric studies can earn pediatric exclusivity even if the studied uses are not approved. In this regard, the draft guidance restates an existing Agency principle.
- The draft guidance addresses situations where a WR is “capable of more than one interpretation.” In this situation, FDA “generally consider[s] a fair response [to the written request] to be one that interprets the WR in a manner likely to generate information that will provide a health benefit (including meaningful pediatric labeling) in the relevant populations that the WR asked the sponsor to study.” If, instead, the “sponsor responds in such a way that the possibility of a health benefit (including meaningful pediatric labeling in relevant age groups) from the studies conducted is not likely, [FDA is] likely to” deny pediatric exclusivity.
- The draft guidance briefly discusses rescission of a WR. FDA states that, “[o]n occasion, information obtained by FDA subsequent to issuance of a WR causes FDA to rescind the WR.”
“Pediatric Drug Development Under the Pediatric Research Equity Act and the Best Pharmaceuticals for Children Act: Scientific Considerations”
This draft guidance covers scientific issues for sponsors to consider when designing pediatric studies. Unlike its counterpart guidance on regulatory considerations, this draft guidance discusses general topics relevant to an overall pediatric development program, rather than addressing issues specific only to PREA or the BPCA. Some of this discussion focuses specifically on the ethical considerations raised by pediatric studies. The draft guidance provides recommendations to inform how and when sponsors obtain data for approval of a drug’s use in pediatric populations, though FDA says that the principles for pediatric drug development “do not differ greatly” from those for an adult development program. To illustrate some of the key principles articulated in the draft guidance:
- The agency addresses neonate studies, recommending that “[i]n general, such studies should be undertaken at the same time as studies in older pediatric populations, unless efficacy or safety data from older pediatric populations are necessary before initiation of studies in the neonatal population.”
- In the Safety Information section of the draft guidance, FDA states that “because some effects may be measurable only in children of a certain age or maturity level, long-term follow-up studies, particularly for drugs tested in neonates, infants or young children, may be needed.”
- The Safety Information section also provides that “[p]harmacovigilance programs developed to assess known or potential safety signals in adult subjects should also include pediatric subjects, when appropriate.”
FDA recommends early engagement with the Agency for many of the topics covered in the draft guidance.
Comments on the draft guidances are due July 17. If you have any questions concerning the material discussed in this client alert or would like our assistance in preparing a comment, please contact the members of our Food, Drugs, and Devices practice.
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