US FDA Tweaks Guidance On Sameness Of Gene Therapies, But Questions Remain
Executive Summary
In response to industry input, the agency made a few changes to its draft guidance but several issues remain uncertain, such as what constitutes ‘minor differences’ between gene therapy products.
At the request of stakeholders, the US Food and Drug Administration has added a bit more clarity on when it will consider gene therapy products to be the same for the purposes of determining an orphan drug designation or orphan exclusivity. But its final guidance still leaves unresolved questions about what may constitute “minor differences” between products.
The agency issued the guidance, “Interpreting Sameness of Gene Therapy Products Under the Orphan Drug Regulations,” on 29 September. The six-page document is very similar to the draft guidance issued in January 2020. (Also see "Orphan Exclusivity For Gene Therapies Hinges On Two Big Factors" - Pink Sheet, 28 Jan, 2020.)
Both documents state that FDA’s determination of “sameness” for two gene therapy products, assuming they are intended for the same use or indication, will consider the principal molecular structural features of the products. The agency said it generally intends to consider key features such as transgenes and vectors used in gene therapy products to be the principal molecular structural features.
Like the draft, the final guidance says that if the two gene therapy products express different transgenes the agency generally intends to consider them to be different drugs. The agency said it would also consider them to be different drugs if the products have or use different vectors.
Impact Of Vectors Matter
The FDA provided examples of the latter, saying it generally intends to consider vectors from the same viral group (e.g., adeno-associated virus 2 (AAV2) vs. adeno-associated virus 5 (AAV5), or gammaretrovirus vs. lentivirus) to be different. But the final guidance adds language specifying they would be found to be different “when the differences between the vectors impact factors such as tropism, immune response avoidance, or potential insertional mutagenesis.”
That clarification seems to address a concern raised by Regeneron Pharmaceuticals, Inc. in its comments on the draft guidance. It asked the FDA to define two vectors from the same viral class but different serotypes as a characteristic sufficient to classify gene therapy products as different 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. Therefore, we recommend that gene therapy products from different isotype classes should be classified as different products,” Regeneron stated.
“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.”
Pfizer Inc. also suggested that two serotypes from the same class, such as AAV2 and AAV5, be considered different.
The FDA did not address vectors from different serotypes but noted the impact different vectors have on tropism and immune response avoidance.
The final guidance adds an additional example, saying the agency intends to determine whether variants of a vector from the same viral group (e.g., AAV2 vs. a variant of AAV2) are the same or different on a case-by-case basis.
What Are ‘Minor Differences’ And ‘Additional Features’?
The agency explained that if there are only minor differences in the transgenes and/or vectors it generally does not intend these principal molecular structural features to be different. Regeneron asked the FDA to explicitly define “minor differences” and BioMarin Pharmaceutical Inc. asked the agency to provide specific examples.
The final guidance adds one parenthetical example of a minor difference, polymorphism.
The guidance states that if two gene therapy products express the same transgene and have or use the same vector, determining whether they are the same drug may also depend on “additional features of the final product that can contribute to the therapeutic effect." Several commenters asked the FDA to expound on this.
BioMarin said the agency’s approach is sound policy given the complexity of gene therapy products but that “minor tweaks or changes to the product design that do not contribute to the therapeutic effect in a substantive way should not be allowed to break the exclusivity of a previously approved ‘same’ drug for the ‘same use’ or indication.”
The company recommended that FDA accept different types of data and data sources to inform its decision-making and said it would be helpful if the agency could provide examples of the type of data (e.g. discovery data or nonclinical data) that would inform FDA’s determination of whether additional features can contribute to the therapeutic effect.
bluebird bio also encouraged FDA to provide an example and clarification of what is meant by “additional features” of gene therapy products. And CSL Behring asked the agency to include the transfer system and manufacturing technology as “additional features” that could be differentiating factors for determining sameness of gene therapy orphan products.
The agency added three parenthetical examples in the final guidance. “These additional features may include regulatory elements (e.g., promoters, enhancers, or splicing elements), or for ex vivo genetically modified cells, may include the cell type that is transduced,” the guidance states.
Stakeholders Want Additional Guidance
Stakeholders expressed support for the FDA’s approach to interpreting the sameness of gene therapy products, but sought more detail than was provided in the final guidance and noted the need for additional information in the future.
The Biotechnology Innovation Organization said it believes the agency’s framework is drafted in a way that supports development of innovative gene therapy products. However, it requested that FDA clarify that gene editing products are out-of-scope for the guidance and will be subject to case-by-case determinations. The final guidance does not address these products.
BIO said there may not yet be sufficient information to understand all possible circumstances when gene therapies may be differentiated. “Additionally, at present some factors that may ultimately result in substantially different clinical safety and efficacy profiles cannot or have not been measured,” the association stated.
BIO recommended that FDA conduct a public meeting and issue a discussion guide to collect additional information from stakeholders about gene therapy products. It recommended that the discussion guide address the agency’s thinking on what FDA considers will constitute a “principal molecular structural feature;” what factors FDA would consider in “case-by-case” scenarios when two gene therapy products express the same transgene and use vectors in the same viral class; and what FDA considers will constitute additional “regulatory elements” that may differentiate gene therapy products.
The National Organization for Rare Disorders said it hopes that as the science develops, FDA will share its thinking around additional features of the final product that do or do not contribute to sameness. NORD asserted that it is important for FDA to maintain open communications with drug developers and be flexible as new data and understanding of gene therapies emerge.
“For example, additional guidance will be necessary on the meaning of ‘minor differences’ in transgenes and vectors. This lack of clarity could affect how sponsors approach their gene therapy development program and impact investments and innovation,” NORD stated. “Therefore, 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 ODA [Orphan Drug Act].”
NORD suggested that FDA use approaches such as an iterative guidance like its COVID-19 guidances, a discussion guide, or a forum to respond to stakeholder questions on sameness over time.
Some commenters noted the importance of engaging with the agency early in the development process. The agency added a statement in the final guidance advising sponsors to contact the Office of Orphan Products Development if they have questions about orphan drug designation and to contact the Office of Tissues and Advanced Therapies in the Center for Biologics Evaluation and Research (e.g., through an IND amendment requesting advice or through a formal meeting request) if they have questions related to specific gene therapy product development programs.