Gene Therapy Firms Seek Clarity on FDA Exclusivity, Orphan Designations

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meeting and issue a discussion guide to collect additional stakeholder input to be considered for inclusion in a Q&A draft guidance. The discussion guide and Q&A draft guidance should address the FDA’s thinking on several questions, such as: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

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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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