On Tuesday, FDA’s Center for Biologics Evaluation and Research (CBER) finalized six gene therapy guidances drafted in July 2018. With the Office of Orphan Products Development (OOPD), CBER also issued a new draft guidance, “Interpreting Sameness of Gene Therapy Products Under the Orphan Drug Regulations,” which provides FDA’s thinking on determining “sameness” of gene therapy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. Most notably, the new draft guidance affirms FDA’s thinking that two gene therapy products that express different transgenes or use different vectors are different drugs for purposes of the orphan drug program. In addition, FDA clarified that two gene therapy products using vectors from different viral classes will also be considered different, while the agency will examine the “sameness” of two vectors from the same viral class “on a case-by-case basis.” Finally, FDA will consider “additional features” in certain situations where products use the same transgene and vector. However, FDA may consider two gene therapy products intended for the same use or indication to be the “same” if there are only “minor differences” in the transgenes and/or the
Under the Orphan Drug Act, questions of orphan “sameness” are critical for evaluating the eligibility of a drug product for designation as an orphan drug or an award of orphan 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, unless the second drug product is shown to be clinically superior. For 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 The draft guidance somewhat fills that gap, stating that FDA generally intends to consider certain key features of gene therapy products, such as transgenes and vectors, to be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.
FDA further explains that, when ascertaining “sameness” under orphan drug regulations, it will consider two gene therapy products intended for the same use or indication to be different if they:
- express different transgenes, whether or not they have or use the same vector; or
- have or use different vectors, including vectors from a different viral class, even if they express the same transgene.
Additionally, FDA indicates that even products that express the same transgene and have or use the same vector may be considered different in certain situations. Specifically, “when applicable,” FDA generally intends to consider “additional features of the final product that can contribute to the therapeutic effect” (e.g., regulatory elements, cell type that is transduced) in its sameness determination.
In these scenarios, however, FDA generally will not consider these principal molecular structural features to be different if there are only “minor differences” in the transgenes and/or the vectors. Similarly, agency determinations of whether two vectors from the same viral class (e.g., AAV2 vs. AAV5) are the same will be made “on a case-by-case basis.” Although the guidance does not address clinical superiority for gene therapy products, it seems possible that minor structural differences that do not support a determination that two products are different may nonetheless provide a basis for concluding that a product is clinically superior, and therefore not the “same drug” as the previously approved product.
Of the six finalized gene therapy guidance documents ( summarized here), three cover products for specific disease categories (hemophilia, rare diseases, and retinal disorders), and three address manufacturing and clinical study design issues related to gene therapy: chemistry, manufacturing and control (CMC) information in INDs, long term follow-up study design, and testing of retroviral vector-based products. The finalized guidances contain only minor changes from their draft forms.
In a press release announcing the guidance documents, FDA Commissioner Stephen M. Hahn, M.D. and CBER Director Peter Marks, M.D., Ph.D. assured all stakeholders that FDA will continue to work with them “to help make the development and review of [gene therapy] products more efficient, while putting in place the regulatory controls needed to ensure that the resulting therapies are both safe and effective.” Please feel free to reach out to the Hogan Lovells attorney with you whom you regularly work if you have any questions about how the FDA’s evolving regulatory framework for gene therapies may affect product development in the future.
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