Fitting New Scientific Advances Into an Old Regulatory Paradigm (Part 2): Gene Therapy and Orphan Drug “Sameness”

Earlier this week, we discussed in a post how FDA, under the Agency’s decades-old regulations defining the term “same drug,” evaluates orphan drug “sameness” in the context of fusion proteins.  At the end of that post we suggested that gene therapy “sameness” might be the next hot topic on FDA’s orphan drug “sameness” plate, and said that we would leave a discussion of that topic for another day.  Well, that’s today.

In our earlier post we went through how FDA approaches orphan drug “sameness” issues under the Agency’s regulations and how those determinations affect approval and exclusivity decisions. We won’t repeat all of that here, but note that for large molecules (i.e., macromolecules), structural “sameness” means that the second drug contains “the same principal molecular structural features (but not necessarily all of the same structural features)” as the previously approved drug.  FDA further defines structural “sameness” for different types of macromolecules, including proteins, polysaccharides (i.e., complex sugars), polynucleotides (e.g., nucleic acids like RNA and DNA), and partially definable drugs (e.g., live vaccines).

Gene therapy is a pretty hot topic these days. It was just earlier this month that FDA’s Oncologic Drugs Advisory Committee recommended that FDA approve the first gene therapy product: Novartis Pharmaceuticals Corporation’s BLA 125646 for Tisagenlecleucel for the treatment of pediatric and young adult patients 3 to 25 years of age with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia.

A search of FDA’s Orphan Drug Designations and Approvals Database shows that the Agency’s Office of Orphan Products Development (“OOPD”) has designated several gene therapy products as orphan drugs, including tisagenlecleucel for the treatment of diffuse large B-cell lymphoma. Although the issue of gene therapy “sameness” for orphan drug designation and exclusivity purposes has not yet been addressed by OOPD, the issue is almost certain to come up as FDA begins licensing BLAs for various products.  And although FDA has not yet spoken to the issue of gene therapy “sameness”, we think it’s possible to make some predictions as to where OOPD might end up if presented with a gene therapy “sameness” issue.

Gene therapy utilizes the delivery of DNA (or RNA) into cells. This delivery can be accomplished by several methods; however, the two major classes of methods are those that use recombinant viruses (sometimes called biological nanoparticles or viral vectors) and those that use “naked” DNA or DNA complexes (i.e., non-viral methods).  The use of recombinant viruses seems to be the focus of many manufacturers right now, so we’ll focus on that type of gene therapy.

A recombinant virus gene therapy product has two components: (1) the genetic component (DNA or RNA); and (2) the viral vector. Determining the “sameness” of two genetic components would certainly seem to be an easy issue, as the sequences/compositions of the genetic material can easily be compared.  That leaves the vector component.  The extent to which the vector component should be considered in an orphan drug “sameness” determination is likely to be the central issue for FDA and OOPD to address and resolve.  That is, whether or not the vector is part of the orphan drug, or whether it is merely part of the product “formulation” and serves as a route of delivery for the “true” orphan drug – the genetic component in a gene therapy product.

If FDA determines that both the genetic and vector components are relevant to a “sameness” determination because they both comprise the gene therapy product, then two gene therapy products that contain the identical genetic constituent would be considered different if different vectors are used. If, however, FDA determines that it is only the genetic component that is relevant to “sameness,” then different vectors are irrelevant, unless the vector can be argued to provide a basis for clinical superiority (i.e., greater efficacy, safety, or a major contribution to patient care).

Of the two options above, FDA seems may be more inclined to adopt the second option (i.e., the genetic component is the “drug” and the basis for a “sameness” determination, while the vector component is part of the “formulation” and the basis for a clinical superiority argument) than the first option.  To some extent, the second option is the simpler option to apply and could avoid (some) controversy.  For example, we understand that sometimes repeated rounds of gene therapy are needed, and that those subsequent rounds may require different vector serotypes.  If both the genetic component and the viral vector comprise the drug, then the use of different vector serotypes would undoubtedly complicate matters and create a “moving target” for orphan drug “sameness” purposes.  On the other hand, the second option has the potential to delay licensure of competing gene therapy products that include the identical genetic component.  In that case, it will fall on FDA to determine whether or not the use of a different vector provides a basis for arguing clinical superiority, thereby allowing licensure of a second product notwithstanding another sponsor’s unexpired period of orphan drug exclusivity.