On September 30, 2021, the U.S. Food and Drug Administration (FDA) announced final guidance titled “Interpreting Sameness of Gene Therapy Products under the Orphan Drug Regulations.” The guidance finalizes the January 2020 draft guidance and provides FDA’s current perspective on certain criteria that help determine sameness of human gene therapy products for orphan drug designation and exclusivity purposes. In the Federal Register notice announcing the final guidance, FDA noted that it received comments on the draft guidance that “generally supported the approach described in the guidance.” FDA considered these comments and requests for additional clarification when finalizing the guidance, “adding clarification and examples, as feasible.”
The Orphan Drug Act (ODA) seeks to incentivize the development of drugs for rare diseases, defined in the ODA as those affecting fewer than 200,000 people in the United States. The incentives include a 25% tax credit on applicable research and development expenditures, waived user fees when submitting applications to FDA, and the potential for a seven-year period of orphan drug exclusivity for the approved indication. Manufacturers must request and be granted designation before they are eligible for any incentives.
When FDA grants marketing approval for a designated orphan drug for a use or indication within the designation disease or condition, FDA will determine if the drug is eligible for orphan drug exclusivity. Orphan drug exclusivity is product and indication specific, meaning FDA cannot approve a drug containing the same active moiety for the same intended use or indication during the period of marketing exclusivity.
FDA uses different criteria in determining sameness for macromolecule and small molecule drugs . The FDA defines “same drug” for macromolecule drugs as “a drug that contains the same principal molecular structural features (but not necessarily all of the same structural features) and is intended for the same use as a previously approved drug, except that, if the subsequent drug can be shown to be clinically superior, it will not be considered to be the same drug." 
If a sponsor requests orphan drug designation for a drug that is the same as a drug already approved for the same use or indication, the sponsor must provide a plausible hypothesis that its drug is clinically superior to the already approved drug. Designation as clinically superior is based on greater efficacy, safety, or a major contribution to patient care. In order to receive the seven-year market exclusivity, a sponsor must demonstrate that its product is actually clinically superior.
Interpreting Sameness of Gene Therapy Products
Human gene therapy products may qualify for orphan drug designation if they are intended for the treatment of a rare disease or condition and the sponsor sufficiently establishes a basis for expecting the drug to be effective in treating the rare disease. The existing regulations do not describe how the “same drug” definition applies specifically to gene therapy products for orphan drug designation and exclusivity. Mirroring the January 2020 draft guidance, FDA’s final guidance provides some insight into the current interpretation of how the “sameness” criteria applies to gene therapies.
Assuming that two gene therapy products are intended for the same use or indication, FDA will consider the “principal molecular structural features” of the gene therapy products when determining “sameness.” In the final guidance, FDA states its intention to generally “consider certain key features such as transgenes and vectors used in gene therapy products to be ‘principal molecular structural features’ under this regulation.” However, FDA does not intend to classify two gene therapy products as different based solely on minor differences in the transgenes and/or vectors, and will determine whether differences are minor differences on a case-by-case basis.
For two gene therapy products intended for the same use or indication, if the products express different transgenes, FDA generally intends to consider them to be different drugs because they will not contain the same principal molecular structural features. This would be the case regardless of whether the two gene therapy products at issue have or use the same vector. FDA also intends to consider vectors from a different viral group to be different for purposes of determining “sameness.” Additionally, FDA clarified in the final guidance that it will consider two gene therapy products from the same viral group to be different “when the differences between the vectors impact factors such as tropism, immune response avoidance, or potential insertional mutagenesis.” FDA intends to determine whether variants of a vector from the same viral group are the same or different on a case-by-case basis.
In a case where two gene therapy products express the same transgene and have/use the same vector, FDA may also consider additional features of the final product when determining “sameness,” such as regulatory elements (e.g., promoters or enhancers). In these instances, FDA generally intends to determine “sameness” of gene therapy products on a case-by-case basis.
 21 CFR 316.3(b)(14).
 21 CFR 316.3(b)(14)(ii).