FDA Finalizes Guidance On Interpretation Of Orphan Drug – Mondaq News Alerts

27 October 2021

Morrison & Foerster LLP

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On September 30, 2021, the U.S. Food and Drug Administration(FDA)announcedfinal guidance titled "Interpreting Sameness of Gene Therapy Productsunder the Orphan Drug Regulations." The guidance finalizesthe January 2020 draft guidance and provides FDA's currentperspective on certain criteria that help determine sameness ofhuman gene therapy products for orphan drug designation andexclusivity purposes. In the Federal Register notice announcing thefinal guidance, FDA noted that it received comments on the draftguidance that "generally supported the approach described inthe guidance." FDA considered these comments and requests foradditional clarification when finalizing the guidance, "addingclarification and examples, as feasible."

The Orphan Drug Act (ODA) seeks to incentivize the developmentof drugs for rare diseases, defined in the ODA as those affectingfewer than 200,000 people in the United States. The incentivesinclude a 25% tax credit on applicable research and developmentexpenditures, waived user fees when submitting applications to FDA,and the potential for a seven-year period of orphan drugexclusivity for the approved indication. Manufacturers must requestand be granted designation before they are eligible for anyincentives.

When FDA grants marketing approval for a designated orphan drugfor a use or indication within the designation disease orcondition, FDA will determine if the drug is eligible for orphandrug exclusivity. Orphan drug exclusivity is product and indicationspecific, meaning FDA cannot approve a drug containing the sameactive moiety for the same intended use or indication during theperiod of marketing exclusivity.

FDA uses different criteria in determining sameness formacromolecule and small molecule drugs 1.The FDAdefines "same drug" for macromolecule drugs as "adrug that contains the same principal molecular structural features(but not necessarily all of the same structural features) and isintended for the same use as a previously approved drug, exceptthat, if the subsequent drug can be shown to be clinicallysuperior, it will not be considered to be the same drug."2

If a sponsor requests orphan drug designation for a drug that isthe same as a drug already approved for the same use or indication,the sponsor must provide a plausible hypothesis that its drug isclinically superior to the already approved drug. Designation asclinically superior is based on greater efficacy, safety, or amajor contribution to patient care. In order to receive theseven-year market exclusivity, a sponsor must demonstrate that itsproduct is actually clinically superior.

Human gene therapy products may qualify for orphan drugdesignation if they are intended for the treatment of a raredisease or condition and the sponsor sufficiently establishes abasis for expecting the drug to be effective in treating the raredisease. The existing regulations do not describe how the"same drug" definition applies specifically to genetherapy products for orphan drug designation and exclusivity.Mirroring the January 2020 draft guidance, FDA's final guidanceprovides some insight into the current interpretation of how the"sameness" criteria applies to gene therapies.

Assuming that two gene therapy products are intended for thesame use or indication, FDA will consider the "principalmolecular structural features" of the gene therapy productswhen determining "sameness." In the final guidance, FDAstates its intention to generally "consider certain keyfeatures such as transgenes and vectors used in gene therapyproducts to be 'principal molecular structural features'under this regulation." However, FDA does not intend toclassify two gene therapy products as different based solely onminor differences in the transgenes and/or vectors, and willdetermine whether differences are minor differences on acase-by-case basis.

For two gene therapy products intended for the same use orindication, if the products express different transgenes, FDAgenerally intends to consider them to be different drugs becausethey will not contain the same principal molecular structuralfeatures. This would be the case regardless of whether the two genetherapy products at issue have or use the same vector. FDA alsointends to consider vectors from a different viral group to bedifferent for purposes of determining "sameness."Additionally, FDA clarified in the final guidance that it willconsider two gene therapy products from the same viral group to bedifferent "when the differences between the vectors impactfactors such as tropism, immune response avoidance, or potentialinsertional mutagenesis." FDA intends to determine whethervariants of a vector from the same viral group are the same ordifferent on a case-by-case basis.

In a case where two gene therapy products express the sametransgene and have/use the same vector, FDA may also consideradditional features of the final product when determining"sameness," such as regulatory elements (e.g., promotersor enhancers). In these instances, FDA generally intends todetermine "sameness" of gene therapy products on acase-by-case basis.

Footnotes

1. 21 CFR 316.3(b)(14).

2. 21 CFR 316.3(b)(14)(ii).

Because of the generality of this update, the informationprovided herein may not be applicable in all situations and shouldnot be acted upon without specific legal advice based on particularsituations.

Morrison & Foerster LLP. All rights reserved

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FDA Finalizes Guidance On Interpretation Of Orphan Drug - Mondaq News Alerts