"Sameness" in the cellular and gene therapy context is an emerging issue of critical importance. Sameness determinations form the backbone of numerous regulatory decisions, including exclusivity, patent term extensions, approval actions, and priority review vouchers. Unlike small molecules and some other biological products, sameness evaluations for cellular and gene therapy products do not fall neatly within an established regulatory framework because of the complex structural features of these products.

In its initial guidance, the U.S. Food and Drug Administration (FDA) stated that it would make sameness determinations for gene therapy products for orphan drug purposes based on the transgene and vector. A difference in either the transgene or vector may be sufficient to create a different product. Recently, FDA identified six key structural features of gene therapy products that are important to the sameness evaluation: (1) vector serotype; (2) transgene protein sequence; (3) transgene cDNA sequence (including codon optimization); (4) promoter/enhancer; (5) intron; and (6) polyadenylation signal. FDA has applied this analysis to numerous products, and the legal landscape continues to be refined as new precedent emerges.

With respect to cellular therapies, FDA has focused on final cell compositions, including whether the products are administered at the same defined ratio of cell subsets. However, as FDA recognized in 2023 draft guidance, many cellular products consist of a complex mixture of different cell types in which the contribution of each to the activity of the product is difficult to determine. In these cases, FDA does not necessarily consider the product to have multiple active ingredients. Rather, the activity of the product is considered to be derived from the totality of the mixture of the cells, and the mixture itself is considered the active ingredient.

FDA recently applied its cellular product "sameness" framework in the context of Priority Review Vouchers (PRVs). To secure a PRV, sponsors must show that their product's active ingredient has not been previously approved. Relevant here was the agency's review of transduced autologous CD34+ cells from patients. Specifically, FDA denied a PRV in one case based on the determination that the product contained a previously approved active ingredient, illustrating the ongoing complexity of "sameness" determinations for such products.

In late 2025, FDA issued three draft guidance documents regarding the development of cellular and gene therapy products, including innovative designs for clinical trials. As the number and complexity of cellular and gene therapy products increase, the legal paradigm and related strategies must reflect those developments.