FDA finalizes guidance on Orphan Drug “sameness” of gene therapies

Recently, the U.S. Food and Drug Administration’s (FDA’s) Office of Orphan Product Development published the four-page final guidance “Interpreting Sameness of Gene Therapy Products Under the Orphan Drug Regulations,” which provides FDA’s thinking on determining “sameness” of gene therapy products for the purpose of orphan-drug designation and exclusivity. Mirroring the draft guidance published in January 2020, the final guidance affirms FDA’s position that two gene therapy products that express different transgenes or use different vectors are different drugs for purposes of the orphan drug program. FDA also confirms that two gene therapy products that use vectors from different viral groups will be considered different. The agency will examine the sameness of two vectors from the same viral group by looking at the impact of any differences on certain factors, while variants will be examined “on a case-by-case basis.”

Under the Orphan Drug Act, questions of orphan “sameness” are critical for evaluating the eligibility of a drug or biological product for orphan-drug designation and exclusivity, as well as determining the scope of that orphan exclusivity. A drug product’s orphan exclusivity prohibits FDA from approving the “same drug” for the same use or indication for seven years after the date of approval, unless the second drug product is shown to be clinically superior. For gene therapy products and other large molecule drugs, FDA regulations define “same drug” as a drug that contains the same “principal molecular structural features (but not necessarily all of the same structural features).”

The existing regulations do not elaborate on how this definition applies specifically to gene therapy products. The final guidance fills that gap, stating that FDA generally intends to consider certain key features of gene therapy products, such as transgenes and vectors, to be “principal molecular structural features” for purposes of this analysis. Outside of those definitive statements, however, there remains much that FDA continues to say it will consider on a “case-by-case” basis.

As in the draft version of this guidance, FDA explains that, when determining “sameness” under the orphan drug regulations, the agency will consider two gene therapy products intended for the same use or indication to be different if they:

  1. express different transgenes, whether or not they have or use the same vector; or
  2. have or use different vectors, including vectors from a different viral class, even if they express the same transgene.

However, in the final guidance, FDA notably clarifies that it will consider two gene therapy products from the same viral group (e.g., adeno-associated virus 2 (AAV2) vs. adeno-associated virus 5 (AAV5), or gammaretrovirus vs. lentivirus) to be different “when the differences between the vectors impact factors such as tropism, immune response avoidance, or potential insertional mutagenesis.” FDA says it will determine whether variants of a vector from the same viral group (e.g., AAV2 vs. a variant of AAV2) are the same or different “on a case-by-case basis.”

In a notice announcing the final guidance, FDA said that it received several comments on the draft guidance that “generally supported the approach described in the guidance,” although FDA also aimed to “provide additional clarification” in the final version. For example, the final guidance adds [in Footnote 1] a brief definition of “human gene therapy products,” as well as multiple notes explaining which office within FDA to contact for specific questions.

Please feel free to reach out to the Hogan Lovells attorney with whom you regularly work if you have any questions about how FDA’s evolving regulatory framework for gene therapies may affect product development in the future.


Authored by Dave Fox, Gary Veron, George O’Brien, Jason Conaty, and Komal Karnik Nigam


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