Biotech companies and industry groups are raising questions about the US Food and Drug Administration’s (FDA) recent draft guidance on interpreting sameness of gene therapy products under its orphan drug regulations.
The draft guidance, issued for comment in January, explains how FDA intends to determine the sameness of two gene therapies intended for the same use or indication for the purposes of awarding orphan drug designation and exclusivity.
While current regulations “do not elaborate on how the ‘same drug’ definition applies specifically to gene therapy products,” FDA explains that it will consider the principal molecular structural features of the gene therapies to make its determination.
The draft guidance provides three examples of situations where it would consider two gene therapies intended for the same use or indication to be different drugs: based on whether they express different transgenes and have or use different viral vectors, whether they express different transgenes and whether they have or use vectors from a different viral class. The agency also explains that for gene therapies that express the same transgene and have or use the same vector, it will also consider other features of the products, such as regulatory elements and the cell type that is transduced, to inform its decision on their sameness.
In comments submitted to the public docket for the draft guidance, the Biotechnology Innovation Organization (BIO) says the cases outlined in the draft guidance “are sufficiently exhaustive in demonstrating under what circumstances FDA would consider two gene therapy products either the same or different,” but requests the agency clarify that gene editing products are outside the scope of the guidance.
BIO also acknowledges that “Regulatory discussions and certainly the science around gene therapy products are still evolving and there may not yet be sufficient information to understand all possible circumstance when gene therapies may be differentiated,” and asks that FDA engage with stakeholders as it gains experience with these products.
As part of that engagement, BIO asks that FDA hold a public meeting and issue a draft discussion guide to solicit further input from stakeholders before finalizing its guidance.
BIO raises four specific questions it wants FDA to address in draft guidance, including what the agency considered to be a principal molecular structural feature, what factors it will consider in case-by-case scenarios, what regulatory elements of a gene therapy would differentiate two products with the same transgene expression and vector, and how the agency will consider other factors in determining sameness.
The American Society of Gene and Cell Therapy (ASGCT) also wonders what FDA plans to consider in case-by-case scenarios for determining sameness and asks for more clarity on the matter. Additionally, ASGCT seeks clarification on what regulatory elements may be considered additional features for the purposes of the sameness determination and asks whether those features would need to contribute to the therapeutic effect of a product to be considered as contributing to the products’ differences.
Drugmaker Regeneron Pharmaceuticals comments that it would like FDA to consider viral vectors from the same viral class but with different serotypes to be sufficient to differentiate two gene therapy products.
“Different serotypes of adeno-associated virus (AAV) are likely to exhibit differences in tissue tropism, transgene expression, and immunogenicity; important characteristics that can significantly impact the safety and efficacy of a product,” the company writes.
In its comments, CSL Behring calls on FDA to “include the transfer system and manufacturing technology” as additional features to consider when making determination of sameness for gene therapies.
Gene therapy developer Freeline Therapeutics also calls on FDA to consider manufacturing systems as a differentiating factor between gene therapies and asks for further elaboration on FDA’s interpretation of vectors and says it believes the term vector should cover “both the virus capsid, and the expression cassette.”
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