Gene Therapy Firms Seek Clarity on FDA Exclusivity, Orphan Designations

Xconomy National — 

Gene therapy product developers are seeking more clarity from the US Food and Drug Administration on when viral vectors from the same class will be considered sufficiently different for purposes of awarding orphan drug designation or exclusivity.

In addition, stakeholders want the FDA to better define, and provide examples of, the types of minor differences and additional features that would impact the agency’s “sameness” determination under the orphan drug regulations, and they seek assurance that the agency will share its lessons learned as it gains more experience in making such determinations for gene therapy products.

In a much-anticipated draft guidance issued in January, the agency said that if two gene therapy products are for the same use or indication, it will consider certain key features, such as transgenes and vectors, to be the “principal molecular structural features” in determining sameness for orphan designation and exclusivity purposes. (Also see “Orphan Exclusivity For Gene Therapies Hinges On Two Big Factors” – Pink Sheet, 28 Jan, 2020.)

If two gene therapy products express different transgenes and/or use vectors from different viral classes, the agency generally intends to consider them to be different drugs. However, it will decide whether two vectors from the same viral class (e.g., adeno-associated virus 2 (AAV2) vs. adeno-associated virus 5 (AAV5)) are the same or different on a case-by-case basis.

In an effort to guard against rewarding trivial changes between products, the agency said it will not consider two gene therapies to be different drugs based solely on “minor differences” between their transgenes and/or vectors. (Also see “Gene Therapies: ‘Trivial’ Changes Will Not Be Rewarded With Orphan Drug Designation And Exclusivity” – Pink Sheet, 14 Apr, 2020.)

If two gene therapy products express the same transgene and use the same vector, determining whether they are the “same” for orphan designation purposes may depend upon “additional features” of the final product that can contribute to the therapeutic effect, such as regulatory elements, the guidance states.


In comments on the draft guidance, product sponsors raised concerns about the vagueness of the agency’s proposed case-by-case approach to determining sameness when viral vectors come from the same class.

“We appreciate FDA’s clarification that FDA intends to make the determination of whether two vectors from the same viral class (e.g., AAV2 vs. AAV5) are the same or different on a case-by-case basis,” BioMarin Pharmaceutical Inc.’s comments state. “Considering that there is tremendous development of gene therapy products using AAV-based vectors, it would be helpful to further clarify FDA’s thinking regarding factors that FDA may consider in making the determination that vectors within the same viral class are the same or different.”

Pfizer Inc. proposed that two serotypes from the same viral class, such as AAV2 and AAV5, be considered different. “Such differentiation is supported by the science,” the company said. “Evolutionary differences are captured by the parvovirus phylogenetic classification and are known to impact biological properties such as immunogenicity, tropism and infectivity.”

Similarly, Regeneron Pharmaceuticals, Inc. requested the agency define two vectors from the same viral class, but with different serotypes, as a characteristic sufficient to classify two gene therapies as different products. Different AAV serotypes are likely to exhibit differences in tissue tropism, transgene expression and immunogenicity, which are important characteristics that can significantly impact a product’s safety and efficacy, the company’s comments state.

“Therefore, we recommend that gene therapy products from different isotype classes should be classified as different products,” Regeneron said. “An approach that makes this determination on a case-by-case basis will lead to uncertainty, debate and potential disputes that will impede innovation in the development of certain types of gene therapy products.”


Numerous commenters urged the FDA to clarify what may constitute “minor differences” in transgenes and vectors, and to provide specific examples.

Likewise, industry comments urged the FDA to clarify, and provide examples of, what is meant by “additional features” of gene therapy products, such as what “regulatory elements” may be relevant and considered for determination of sameness.

CSL Behring asked the agency to include the transfer system and manufacturing technology as “additional features” that could be differentiating factors for determining sameness.

BioMarin requested the FDA provide examples of the types of information, such as discovery data or nonclinical data, “that would inform FDA’s determination regarding whether the additional features (e.g., regulatory elements such as a different promoter) can contribute to the therapeutic effect such that the additional features may be considered to be principal molecular structural features.”


Given the limited experience to date in making orphan drug determinations in the gene therapy space, several comments emphasized the need for continuous learning and sharing of information by the FDA with sponsors.

“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,” the Biotechnology Innovation Organization’s comments state. “Additionally, at present some factors that may ultimately result in substantially different clinical safety and efficacy profiles cannot or have not been measured. We thus emphasize the importance of FDA updating and engaging stakeholders as additional experience is gained.”

“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.” – BIO
BIO recommends the agency conduct a public meeting and issue a discussion guide to collect additional stakeholder input to be considered for inclusion in a Q&A draft guidance. The discussion guide and Q&A draft guidance should address the FDA’s thinking on several questions, such as:

—What does the FDA consider will constitute a “principal molecular structural feature” for the purpose of the gene therapy guidance?

—What factors would the FDA consider in “case-by-case” scenarios when two gene therapy products express the same transgene and use vectors in the same viral class?

—What does the FDA consider will constitute additional “regulatory elements” that may differentiate gene therapy products?

—How will the FDA consider other factors in their determination of sameness?

The Alliance for Regenerative Medicine said that once the agency feels it has enough experience, it should share its collective experience as general principles for why orphan drug designation or exclusivity is or is not granted.

“Based on FDA’s experience in adjudicating the sameness determinations, it would be helpful if the agency could provide additional information on relevant considerations,” ARM’s comments state. “These include, for example, unique considerations for the different types of gene therapy products to provide more clarity on a product type basis.”

Similarly, the National Organization for Rare Disorders said that as the science develops and the agency gains experience, it should share its thinking around additional features that do or do not contribute to sameness.

“NORD believes this draft guidance mostly strikes an appropriate balance and ensures regulatory flexibility in the future,” the group said. Nevertheless, additional guidance will be necessary on the meaning of “minor differences” in transgenes and vectors, as lack of clarity could affect how sponsors approach their development program and impact investments and innovation.

“As the agency gains more knowledge and experience, it will be critical for FDA to clearly communicate what constitutes minor differences, how it arrived at this determination, and the process for drug developers to glean this information in order to maximize the incentives afforded to them under the [Orphan Drug Act],” the advocacy group’s comments state.

“NORD suggests using approaches like an iterative guidance that is updated in a step-wise approach, like those utilized during the COVID-19 pandemic, a discussion guide, or a forum in which the agency could respond to stakeholder questions on sameness over time.”

Image: iStock/JHVEPhoto

This article was first published in the Pink Sheet on Sept. 2, 2020.

Sue is a senior editor with Pink Sheet, where she writes primarily about drug, biologic and biosimilar regulation, FDA advisory committees and product approvals. Follow @PinkSheetSutter

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