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Orphan Designation Loophole: Stakeholders Support FDA Draft Guidance

Posted 20 February 2018 | By Zachary Brennan 

Orphan Designation Loophole: Stakeholders Support FDA Draft Guidance

Stakeholders are generally supportive of US Food and Drug Administration (FDA) draft guidance to close an unintended loophole that allows companies to avoid their obligation to study pharmaceuticals in pediatric populations, though industry group BIO is taking issue with the term "loophole," according to comments on the draft.

BIO, which seems to generally support the draft, said the terminology used by FDA in the draft guidance "implies that sponsors are acting inappropriately by taking advantage of a 'loophole,'" which it said it "respectfully disagrees" with and requests that the language be adjusted "to reflect that it has been FDA's legal interpretation of the PREA [Pediatric Research Equity Act] that has allowed for such designations to be granted."


FDA draft guidance from December attempts to stop situations whereby an orphan drug designation for treatments used in pediatric subpopulations may have inadvertently created scenarios in which PREA-required pediatric studies could be exempt by virtue of the designation.

"The interplay of [the] pediatric-subpopulation designation and the PREA orphan exemption has created an unintended loophole where a sponsor holding pediatric-subpopulation designation can submit a marketing application for use of its drug in the non-orphan adult population of that disease, get a pediatric-subpopulation designation for the pediatric subset of the disease, and, due to this designation, be exempt from conducting the pediatric studies normally required under PREA when seeking approval of the adult indication," the draft says.

Comments on Draft Guidance

The American College of Rheumatology, the non-profit Public Citizen and Yale University's Collaboration for Research Integrity and Transparency offered their support for the draft.

Public Citizen also said that "numerous other problems and misaligned incentives of the Orphan Drug Act are in need of remedy," which could include "encouraging the development of truly novel compounds instead of repurposing and making minor changes to old drugs, setting more rigorous standards for clinical trials conducted on drugs for orphan diseases, and preventing companies from receiving orphan drug benefits for products that are ultimately used in much larger patient populations."

Yale's program also urged FDA "to publish a list of drugs that were previously granted pediatric-subpopulation orphan designation, that have not undergone the pediatric studies contemplated in PREA due to this loophole, and to work with sponsors of these drugs to encourage voluntary compliance with PREA requirements."

And BIO requested that FDA more clearly define the terms "pediatric subpopulation(s)" and "pediatric-subpopulation designation(s)" as these terms have not been previously defined or described within Title 21: Food and Drugs PART 316—ORPHAN DRUGS, nor, have the terms been used in past FDA orphan drug guidance.

BIO also requested that FDA provide "specific examples as to what would constitute an 'orphan subset' as defined by molecular characteristics, safety profile, and empirical evidence. BIO also asks for clarification of the term 'different disease', included in bullet two of FDA's criteria for determining whether a product may receive orphan designation for a pediatric subpopulation (Draft Guidance, page 4). We also ask that specific examples be provided indicating what is meant by 'different disease' as defined by endpoints, biomarkers, or other measures."


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