FDA Finalizes Guidance on Gene Therapy Orphan Sameness, but Questions Remain

Morgan Lewis - As Prescribed
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Morgan Lewis - As Prescribed

While it may feel like FDA’s attention has been focused on COVID-19 for nearly two years, as we have written about in a previous blog post, FDA is looking to the future, and particularly, one that signals exciting prospects for biotechnology products, including cell and gene therapies. This is mirrored by the increasing financial strength of the biotechnology industry. The Alliance for Regenerative Medicine reports that regenerative medicine and advanced therapy financing soared during the first half of 2021, resulting in the strongest half year to date, and reached 71% of 2020 full year levels. Moreover, the Alliance reports that there are now more than 1,200 companies worldwide developing advanced biotechnology products and an anticipated 18 global regulatory approval decisions this year. Also, 243 regenerative and advanced therapy phase 3 trials were ongoing at the time of the Alliance’s report.

Not surprisingly, against this backdrop, with the publication of its final guidance on Interpreting Sameness of Gene Therapy Products Under the Orphan Drug Regulations, FDA appears to be anticipating that gene therapy products with similar attributes will be working their way through the development pipeline. With this guidance, FDA sheds light on questions often raised by those in the industry that have bearing on whether products may be eligible for orphan exclusivity and whether second in time products may be blocked by a competitor’s exclusivity. These clarifications cover the following:

  • What constitutes a gene therapy. Specifically, gene therapies are any product that seeks “to modify or manipulate the expression of a gene or to alter the biological properties of living cells for therapeutic use.” These generally “include all products that mediate their effects by transcription or translation of transferred genetic material, or by specifically altering host (human) genetic sequences.” Gene therapies may be “nucleic acids (e.g., plasmids, in vitro transcribed ribonucleic acid (RNA)), genetically modified microorganisms (e.g., viruses, bacteria, fungi), engineered site-specific nucleases used for human genome editing, and ex vivo genetically modified human cells.”
  • Products that use different vectors from the same viral group (e.g., AAV2 v. AAV5 or gammaretrovirus vs. lentivirus) will be considered to be different products “when the differences between the vectors impact factors such as tropism, immune response avoidance, or potential insertional metagenesis.” This approach aligns with that used in the European Union in which there is less emphasis on structural differences and more on the clinical impact of differences. Accordingly, companies may want to develop and/or gather early-stage data demonstrating the potential impact of vector differences.
  • Whether variants of vectors from the same group (e.g., AAV2 v. AAV2 variants) will result in two products being different under the orphan drug regulations will be determined on a case-by-case basis.
  • Minor structural changes between products, such as polymorphism, will not result in a determination that two products are different. Whether a difference is minor will be determined on a case-by-case basis.
  • If two products have the same transgene and the same vector, whether the products are considered different will come down to the additional product features that contribute to therapeutic effect, such as “regulatory elements (e.g., promoters, enhancers, or splicing elements), or for ex vivo genetically modified cells, . . . the cell type that is transduced.” These determinations will also be made on a case-by-case basis.

Key Takeaways

While the finalized guidance provides more clarity, and while it reorients FDA’s sameness determinations to focus more on the clinical effect of a difference, rather than mere structural differences, the guidance does leave open many questions. By example, while ex vivo genetically modified human cells are included within the scope of the guidance, the guidance appears to focus on viral vector-based therapies. Yet, there is potential for significant clinical variability and differences in the clinical impact of modified human cells that extend beyond the cell and transgene, such as those that may be attributable to differences in manufacturing processes. Additionally, there are still a number of areas that will be determined on a case-by-case basis. Exactly how case-by-case determinations are made, by whom, when in the development cycle, and based on what kind of data may become more evident as similar products make their way through the approval pipeline. Accordingly, the industry should monitor FDA’s developing precedent, as the agency’s implementation of the guidance will likely be as or more informative than the text of the guidance itself.

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DISCLAIMER: Because of the generality of this update, the information provided herein may not be applicable in all situations and should not be acted upon without specific legal advice based on particular situations.

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